微生物学报

Domains	Functions	References
N: Not determine.
CARD	Produce ubiquitination and autoactivation	[6-7]
Helicase	Transduct the dsRNA-mediated signaling
CTD	Recognize viral RNA with 5′ triphosphate (ppp)
TM	Anchor to the mitochondrial outer membrane	[8]
Proline-rich region	Bind to the tumor necrosis factor receptor-related factor (TRAF) family members
RING	Equip with E3 ligase activity	[9-10]
ZFD	Regulate gene expression, cell differentiation, and embryonic development at the transcriptional and translational levels
TRAF	Interact with cell surface receptors initiates TRAF protein recruitment
KD	Regulate kinase activity
ULD	Control kinase activation, substrate presentation, and downstream signaling pathways
SDD	Mediate IKKβ and TBK1 dimerization and interaction with IκBα
NBD	Bind to NEMO
HLX	NEMO in complex with IKKβ NBD
CC	N
LZD	Bind to macromolecules
ZFD	Bind effectively to IκBα and may direct IκBα to the ULD/SDD of IKKβ
HLH	Bind to DNA and can form a dimer
DBD	Bind to DNA	[11-12]
IAD	Mediate the interaction of IRFs to other factors
Linker region	N
SRD	Receive signals from other molecules	[13-14]
ARD	Mediate the interaction between two proteins
PEST	N
RHR	Mediate form homologous and heterodimers, which in turn can bind promoter and enhancer regions of genes to regulate gene expression	[13]
NTD	Mediate synergistic binding of proteins to multiple common DNA sites
NLS	Interact with the enucleate carrier so that the protein can be transported into the nucleus
TAD	Activate target gene

Domains	Functions	References
N: Not determine.
CARD	Produce ubiquitination and autoactivation	[6-7]
Helicase	Transduct the dsRNA-mediated signaling
CTD	Recognize viral RNA with 5′ triphosphate (ppp)
TM	Anchor to the mitochondrial outer membrane	[8]
Proline-rich region	Bind to the tumor necrosis factor receptor-related factor (TRAF) family members
RING	Equip with E3 ligase activity	[9-10]
ZFD	Regulate gene expression, cell differentiation, and embryonic development at the transcriptional and translational levels
TRAF	Interact with cell surface receptors initiates TRAF protein recruitment
KD	Regulate kinase activity
ULD	Control kinase activation, substrate presentation, and downstream signaling pathways
SDD	Mediate IKKβ and TBK1 dimerization and interaction with IκBα
NBD	Bind to NEMO
HLX	NEMO in complex with IKKβ NBD
CC	N
LZD	Bind to macromolecules
ZFD	Bind effectively to IκBα and may direct IκBα to the ULD/SDD of IKKβ
HLH	Bind to DNA and can form a dimer
DBD	Bind to DNA	[11-12]
IAD	Mediate the interaction of IRFs to other factors
Linker region	N
SRD	Receive signals from other molecules	[13-14]
ARD	Mediate the interaction between two proteins
PEST	N
RHR	Mediate form homologous and heterodimers, which in turn can bind promoter and enhancer regions of genes to regulate gene expression	[13]
NTD	Mediate synergistic binding of proteins to multiple common DNA sites
NLS	Interact with the enucleate carrier so that the protein can be transported into the nucleus
TAD	Activate target gene

Ubiquiti-nation species	Ubiquiti-nation sites	Physiological functions	Antiviral reaction
N: Not determine.
M1	Methionine (Met)	Inflammation, anti-apoptosis, NF-κB signaling activation^[20]	Epstein-Barr LMP1	TRAF1	Promote M1-linked polyubiquitination and activate downstream typical NF-κB pathway^[21]
K6	Lysine (Lys)	DNA damage repair, mitochondrial autophagy^[22-23]	PDCoV N	poIRF7	Promote K6-linked ubiquitination and inhibit porcine type Ⅰ IFN production^[24]
K11	Lysine (Lys)	Regulates the cell cycle, binds to K48 and promotes proteasomal degradation^[25]	Zika virus NS1	Caspase-1	Reduce K11-linked poly-ubiquitination and inhibit type Ⅰ interferon signaling^[26]
K27	Lysine (Lys)	DNA damage repair, antibacterial and antiviral response^[27-28]	PRV UL21	cGAS	Promote K27-linked ubiquitination and inhibit type Ⅰ interferon signaling^[29]
K29	Lysine (Lys)	Regulating the degradation of kinases^[30]	PRV UL13	STING	Promote K29-linked ubiquitination and inhibit type Ⅰ interferon signaling^[31]
K33	Lysine (Lys)	E3 ligase Nrdp1 mediates polyubiquitination of the K33 linkage of the signaling kinase Zap70, thereby terminating early TCR signaling in CD8(+) T cells^[32]	IBDV VP3	TRAF3	Reduce K33-linked ubiquitination and inhibit IFN-β expression by blocking TRAF3-TBK1 complex formation^[33]
K48	Lysine (Lys)	Mediates protein degradation by 26S proteasome^[34]	GCRV VP4	RIG-1	Promote K48-linked ubiquitination and inhibit type Ⅰ interferon signaling^[35]
K63	Lysine (Lys)	Activate the antiviral signaling pathway^[36-38]	IBV PLpro	MDA5	Reduce K63-linked ubiquitination and inhibit type Ⅰ interferon signaling^[39]
G76	Glycine (Gly)	Connecting each ubiquitin site, formation of a ubiquitin chain by constructing an isopeptide bond between G76 of one ubiquitin and a specific lysine residue of the next ubiquitin^[40]	N	N	N

Ubiquiti-nation species	Ubiquiti-nation sites	Physiological functions	Antiviral reaction
N: Not determine.
M1	Methionine (Met)	Inflammation, anti-apoptosis, NF-κB signaling activation^[20]	Epstein-Barr LMP1	TRAF1	Promote M1-linked polyubiquitination and activate downstream typical NF-κB pathway^[21]
K6	Lysine (Lys)	DNA damage repair, mitochondrial autophagy^[22-23]	PDCoV N	poIRF7	Promote K6-linked ubiquitination and inhibit porcine type Ⅰ IFN production^[24]
K11	Lysine (Lys)	Regulates the cell cycle, binds to K48 and promotes proteasomal degradation^[25]	Zika virus NS1	Caspase-1	Reduce K11-linked poly-ubiquitination and inhibit type Ⅰ interferon signaling^[26]
K27	Lysine (Lys)	DNA damage repair, antibacterial and antiviral response^[27-28]	PRV UL21	cGAS	Promote K27-linked ubiquitination and inhibit type Ⅰ interferon signaling^[29]
K29	Lysine (Lys)	Regulating the degradation of kinases^[30]	PRV UL13	STING	Promote K29-linked ubiquitination and inhibit type Ⅰ interferon signaling^[31]
K33	Lysine (Lys)	E3 ligase Nrdp1 mediates polyubiquitination of the K33 linkage of the signaling kinase Zap70, thereby terminating early TCR signaling in CD8(+) T cells^[32]	IBDV VP3	TRAF3	Reduce K33-linked ubiquitination and inhibit IFN-β expression by blocking TRAF3-TBK1 complex formation^[33]
K48	Lysine (Lys)	Mediates protein degradation by 26S proteasome^[34]	GCRV VP4	RIG-1	Promote K48-linked ubiquitination and inhibit type Ⅰ interferon signaling^[35]
K63	Lysine (Lys)	Activate the antiviral signaling pathway^[36-38]	IBV PLpro	MDA5	Reduce K63-linked ubiquitination and inhibit type Ⅰ interferon signaling^[39]
G76	Glycine (Gly)	Connecting each ubiquitin site, formation of a ubiquitin chain by constructing an isopeptide bond between G76 of one ubiquitin and a specific lysine residue of the next ubiquitin^[40]	N	N	N

泛素化修饰对维甲酸诱导基因I样受体家族(RLRs)信号通路分子调控作用的研究进展

PDF下载

莫荣纤 ¹^,² , 李洪珊 ¹^,² , 李殿玉 ¹^,² , 李向茸 ¹^,²^,^* , 冯若飞 ¹^,²^,^*

微生物学报 | 综述 2024,64(1): 42-60

收起

微生物学报 | 综述 2024, 64(1): 42-60

泛素化修饰对维甲酸诱导基因I样受体家族(RLRs)信号通路分子调控作用的研究进展

全屏

莫荣纤¹^,², 李洪珊¹^,², 李殿玉¹^,², 李向茸¹^,²^,^*, 冯若飞¹^,²^,^*

作者信息

1 西北民族大学生物医学研究中心生物工程与技术国家民委重点实验室, 甘肃兰州 730030

2 西北民族大学生命科学与工程学院, 甘肃兰州 730030

Advances in the regulatory effects of ubiquitination on RLRs signaling pathways

Rongqian MO¹^,², Hongshan LI¹^,², Dianyu LI¹^,², Xiangrong LI¹^,²^,^*, Ruofei FENG¹^,²^,^*

Affiliations

1 Key Laboratory of Biotechnology and Bioengineering of National Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou 730030, Gansu, China

2 College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730030, Gansu, China

出版时间: 2024-01-04 doi: 10.13343/j.cnki.wsxb.20230400

文章导航

摘要

收起

维甲酸诱导基因I样受体家族(retinoid acid-inducible gene-I-like receptors, RLRs)信号通路作为众多抗感染免疫信号通路之一，在诱导促炎细胞因子、趋化因子和I型干扰素产生等方面发挥重要的调控作用。作为蛋白质翻译后修饰之一的泛素化(ubiquitination)，是由泛素蛋白(ubiquitin)与目标蛋白上不同的氨基酸位点产生结合来调控蛋白的命运，如启动蛋白酶体途径降解蛋白或激活转运等功能。而RLRs信号通路分子的泛素化修饰既是调控多种效应因子的方式之一，也是病毒经此诱发动物重要疾病以及自身免疫病、慢性炎症的经典路径之一。本文主要综述RLRs信号通路中重要的效应器分子的典型结构特征、泛素化修饰类型和功能，探讨泛素化修饰调控RLRs信号通路关键分子的作用，为相关疾病的干预或治疗提供参考。

关键词

维甲酸诱导基因I样受体家族 / 泛素化 / 维甲酸诱导基因I / 黑色素瘤分化相关蛋白5 / 遗传学与生理学实验室蛋白2

Abstract

收起

Retinoid acid-inducible gene-I-like receptor (RLR) signaling pathways, the immune signaling pathways in response to infections, play a regulatory role in the production of pro-inflammatory cytokines, chemokines, and type Ⅰ interferons. Ubiquitination as one of the post-translational modifications refers to the process of ubiquitin binding to different amino acid sites on the target proteins, which regulates the fates of proteins. For example, it initiates the proteasome pathway to degrade the target protein or activating the protein transport. The ubiquitination of RLR signaling pathways is a way of regulating multiple effectors and one of the classical pathways through which viruses induce major diseases in animals, autoimmune diseases, and chronic inflammation. This paper introduces the typical structural features and the ubiquitination types of key effectors in the RLR signaling pathways. Furthermore, it expounds the roles of ubiquitination in the regulation of key molecules in the RLR signaling pathways, aiming to provide a reference for the intervention or treatment of related diseases.

Key words

retinoid acid-inducible gene-I-like receptors (RLRs) / ubiquitination / retinoic-acid-inducible gene I (RIG-I) / melanoma differentiation-associated antigen 5 (MDA5) / laboratory of genetics and physiology 2 (LGP2)

引用本文

莫荣纤, 李洪珊, 李殿玉, 李向茸, 冯若飞. 泛素化修饰对维甲酸诱导基因I样受体家族(RLRs)信号通路分子调控作用的研究进展. 微生物学报, 2024 , 64 (1) : 42 -60 . DOI: 10.13343/j.cnki.wsxb.20230400

Rongqian MO, Hongshan LI, Dianyu LI, Xiangrong LI, Ruofei FENG. Advances in the regulatory effects of ubiquitination on RLRs signaling pathways[J]. Acta Microbiologica Sinica, 2024 , 64 (1) : 42 -60 . DOI: 10.13343/j.cnki.wsxb.20230400

正文

收起

维甲酸诱导基因I样受体家族(retinoid acid-inducible gene-I-like receptors, RLRs)是经典的感知病原体的模式识别受体(pattern recognition receptors, PRRs)之一，广泛分布于固有免疫细胞和正常组织细胞的细胞质内^[1]。其余两类常见的PRRs分别为Toll样受体(Toll-like receptors, TLRs)和NOD样受体(NOD like receptors, NLRs)^[1]，它们三者在生物体内形成信号传递网络，共同调控天然免疫、炎症反应以及获得性免疫应答等^[2]。这些传感器属于免疫防御的第一线，通过与病原体相关模式分子(pathogen-associated molecular patterns, PAMPs)识别结合后，激活下游通路因子，调节I型干扰素(type Ⅰ interferon, Ⅰ-IFN)以及其他促炎细胞因子、趋化因子的产生或某些抗病毒基因的表达，从而发挥抗病毒免疫作用^[3]。泛素化(ubiquitination)是仅次于磷酸化的最常见的蛋白质翻译后修饰方式(post-translational modifications, PTMs)^[4]。大多数蛋白质类分子均存在泛素化修饰，近年来雷帕霉素靶蛋白(mechanistic target of rapamycin kinase, mTOR)、丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)、PTEN诱导激酶1-E3泛素连接酶Parkin (PTEN-induced putative kinase 1-E3 ubiquitin-protein ligase Parkin, PINK1-Parkin)、核因子κB (nuclear factor kappa-B, NF-κB)、RLRs、TLRs和环鸟苷酸-单磷酸腺苷合成酶-干扰素基因刺激因子(cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes, cGAS-STING)等信号通路关键效应器分子的泛素化修饰作用受到较为广泛的关注，它们的泛素化修饰对信号通路发挥着重要的调控作用。本文就RLRs信号通路中重要的效应器分子的典型结构特征、泛素化修饰类型、功能，以及对RLRs信号通路关键因子的调控作用展开综述，为相关疾病的干预或治疗提供新思路。

1 RLRs信号通路关键分子的结构特征

收起

目前RLRs家族成员包括3种，即遗传学与生理学实验室蛋白2 (laboratory of genetics and physiology 2, LGP2)、维甲酸诱导基因I (retinoic-acid-inducible gene I, RIG-I)和黑色素瘤分化相关蛋白5 (melanoma differentiation-associated antigen 5, MDA5)。三者在结构上有许多相似之处，LGP2因氨基末端缺乏caspase激活和募集结构域(caspase activates and recruits domains, CARD)，被认为是RIG-I和MDA5信号的调节器^[5]。当RLRs家族识别到RNA病毒后，发出信号激活下游的线粒体抗病毒信号蛋白(mitochondrial antiviral signaling proteins, MAVS也称VISA、ISP-1)，使其招募肿瘤坏死因子受体相关因子(tumor necrosis factor receptor-associated factors, TRAFs)，从而将核因子抑制蛋白激酶(inhibitor κBs kinase, IκBs kinase)激活，最后磷酸化干扰素调节因子(interferon regulatory factors, IRFs)和NF-κB蛋白并使之入核，产生Ⅰ-IFN和细胞炎症因子，发挥抗病毒免疫作用。这些RLRs信号通路关键效应器分子的结构如图1所示，不同结构域在信号传导过程中亦发挥不同的作用，具体结构域的功能见表1。

2 泛素化修饰种类及功能作用

收起

泛素(ubiquitin, Ub)是由76个氨基酸组成的一种高度保守的调控蛋白，最早在1975年由Goldstein团队发现^[15]，截至目前仍被广泛研究。泛素化的过程是由泛素激活酶E1、泛素结合酶E2、泛素连接酶E3组成的高度特异三步酶级联反应。泛素被E1以三磷酸腺苷依赖的方式激活，这个过程包括在泛素的C端甘氨酸(glycine, Gly)和E1半胱氨酸残基(cysteine, Cys)之间形成硫酯键，然后泛素的Gly又与E2上同结构的Cys形成硫酯键，从而转移到E2，接着E2与E3相互作用共同靶向目标蛋白，使得泛素共价键或非共价键结合到目标蛋白位点(赖氨酸/丝氨酸/苏氨酸/半胱氨酸/酪氨酸)上^[16-18]。

目前已证实泛素与底物之间能够发生9种类型的泛素化修饰，分别为G76、K63、K48、K33、K29、K27、K11、K6和M1^[16-19]。大多数泛素化位点存在于甲硫氨酸、赖氨酸和甘氨酸上，除此之外还有少数泛素化可发生在半胱氨酸、丝氨酸或苏氨酸上。因每个位点都可以连接到另一个泛素部分，由此蛋白质可以被不同长度和不同连接类型的泛素单体/聚合物修饰，从而使泛素化成为最精细和最普遍的翻译后修饰之一，由此导致目标蛋白的命运在很大程度上由不同类型的单个泛素结合或多个泛素聚合决定(图2)。因此异常的泛素化可能会导致疾病的发生和发展。

泛素化修饰不仅能够调控蛋白质的亚细胞定位、转运及降解过程，而且还参与细胞凋亡、增殖分化、细胞周期调控、胞内信号传导、DNA损伤修复及炎症免疫反应等多种生命活动。其中K6、K11、K27、K29、K48位点的泛素链启动蛋白酶体降解途径，使目标通路蛋白发生降解；M1、K33、K63位点的泛素链通常是促进通路蛋白的激活、细胞信号的转导和亚细胞定位的改变等；而某些病毒则通过促进或抑制信号分子上不同类型的泛素化来躲避天然免疫，达到入侵宿主的目的(表2)。

3 泛素化修饰对RLRs信号通路分子的调控作用

收起

泛素化修饰对RLRs信号通路分子具有双重调控作用，既可以活化信号分子也可抑制其活化，并且在此过程中有大量E3泛素连接酶参与。RIG-I、MDA5、MAVS等RLRs信号通路关键效应器分子都可发生泛素化修饰，如图3所示。在RLRs信号通路中，通路蛋白的泛素化修饰大部分由K48和K63位点启动，以及少数K27、K29位点等。

3.1 泛素化修饰对LGP2的调控作用

LGP2作为唯一缺乏CARD结构域的RLRs家族，从发现至今对LGP2功能的研究一直还处于探索阶段，虽然LGP2不能直接激活下游的MAVS来发挥抗病毒的信号传导，但有研究发现LGP2在RLRs信号通路中还存在其他重要功能，如它能作为病毒RNA的传感器，辅助RIG-I和MDA5识别结合病毒RNA^[41]；能抑制RIG-I的K48连接的泛素化，使得RIG-I不会被蛋白酶体途径降解，促进RLRs信号通路的激活；此外，它还可以阻止MDA5的K63泛素化，使得MDA5的激活受到影响，从而负向调控RLRs信号传导过程^[42]。不过能使LGP2发生泛素化的分子却少有发现，在近几年的研究中，存在泛素连接酶Riplet能促进LGP2的K63连接的多泛素化，LGP2的这种延迟性的多泛素化在病毒感染的晚期能微调依赖于RIG-I的抗病毒先天免疫反应^[43]。此外，最新研究还发现，猪繁殖和呼吸障碍综合征病毒(porcine reproductive and respiratory syndrome virus, PRRSV)的非结构蛋白Nsp1和Nsp2能与LGP2相互作用，促进LGP2的K63连接的泛素化，最终导致LGP2的降解^[44]，这也表明某些病毒可通过与LGP2作用来达到干扰RLRs信号通路的目的。

3.2 泛素化修饰对RIG-I的调控作用

RIG-I作为RLRs信号通路上的重要PRRs，主要识别结合胞质中5′端三磷酸基团或5′端无帽二磷酸基团的dsRNA或ssRNA等。RIG-I各结构域之间的复合连接，使RIG-I具有自抑制功能，因此一般情况下不会与宿主自身RNA相互作用。

3.2.1 K48连接的泛素化对RIG-I的调控作用

通常E3泛素连接酶与RIG-I的CARD、CTD结构域相互作用后可将泛素分子转移到RIG-I上完成泛素化修饰，如研究表明主要组织相容性复合体(major histocompatibility complex, MHC)编码基因与E3泛素连接酶三基序蛋白40 (tripartite motif containing 40, TRIM40)相互作用后，使TRIM40与RIG-I和MDA5结合并促进二者的K27和K48连接的多泛素化及随后的蛋白酶体降解，使RIG-I和MDA5发生降解，达到干扰RLRs信号通路的目的，进而抑制抗病毒反应^[45]。而E3泛素连接酶Parkin能直接与RIG-I和MDA5相互作用，并催化RIG-I和MDA5的K48连接的多泛素化和蛋白降解，从而限制RLRs触发的先天免疫级联信号的激活^[46]。研究还发现，过表达热休克蛋白结合蛋白1 (Hsp70 binding protein 1, HSPBP1)可抑制RIG-I蛋白K48连接的泛素化以此增加其稳定性，正向调控抗病毒信号通路^[47]。与之相反，细胞内吞体蛋白(sorting nexin 5, SNX5)或FK506结合蛋白8 (FK506 binding protein 8, FKBP8)的过表达却增强了RIG-I的K48连接的泛素化并减弱其K63连接的泛素化，并且SNX5还削弱了MAVS与TRAF2/5之间的相互作用^[48-49]。

而某些病毒/细菌感染宿主细胞后，这些病毒/细菌的蛋白也会促使RIG-I发生K48连接的泛素化，从而逃避机体的抗病毒免疫反应。如草鱼呼肠孤病毒(grass carp reovirus, GCRV)外衣壳蛋白VP4能与RIG-I的CARD和RD结构域结合，促进RIG-I的K48连接的泛素化，降解RIG-I，协助GCRV入侵宿主细胞^[35]；口蹄疫病毒(foot-and-mouth disease virus, FMDV) NS2B通过募集环指蛋白125 (ring finger protein 125, RNF125)靶向RIG-I启动K48连接的泛素化来降解RIG-I^[34]；耶尔森菌的一个效应蛋白YopT能靶向RIG-I并促进其K48链聚合泛素化，负调控RIG-I介导的细胞抗菌反应^[50]。

3.2.2 K63连接的泛素化对RIG-I的调控作用

TRIM25是RIG-I K63连接的泛素化的主要E3泛素连接酶；CCHC型锌指蛋白3 (zinc finger CCHC-type containing 3, ZCCHC3)因含有多个锌指结构域而能抑制一些病毒的复制，研究发现它能将TRIM25募集到RIG-I和MDA5的复合物中，以促进RIG-I和MDA5的K63连接的多泛素化，激活抗病毒信号的传导，诱导I型IFN和炎症因子的产生^[51]。在RNA病毒感染期间，内质网蛋白3 (reticulon3, RTN3)显著上调并聚集在内质网上，从而损害TRIM25介导的RIG-I K63连接的多泛素化，并且抑制IRF3和NF-κB的激活^[52]。最新研究发现，SARS-CoV-2能显著降低RIG-I、MAVS、TBK1、TRAF3/6和IRF3的K63泛素化以及IκBα的K48泛素化，通过去泛素化的依赖性和非依赖性机制靶向RLRs信号通路，从而拮抗天然免疫^[53]。此外，环指蛋白135 (ring finger protein 135, RNF135)也能介导RIG-I的K63连接的多泛素化，而猪德尔塔冠状病毒(porcine deltacoronavirus, PDCoV) N蛋白能抑制RNF135介导的这种泛素化作用^[54]，从而干扰RIG-I的信号传导，拮抗天然免疫。

3.2.3 K27连接的泛素化对RIG-I的调控作用

研究发现SADS-CoV的N蛋白能与RIG-I相互作用，介导RIG-I的K27、K48和K63连接的泛素化及启动的蛋白酶体依赖性降解，从而抑制宿主的IFN反应，由此病毒得以躲避天然免疫而入侵宿主^[55]。

3.3 泛素化修饰对MDA5的调控作用

MDA5在RLRs通路上主要识别结合dsRNA的类似合成物poly(I: C)和小核糖核酸病毒如脑心肌炎病毒(encephalomyocarditis virus, EMCV)等。MDA5的结构域与RIG-I大概有23%−35%的氨基酸同源性，同样在类似区域发生泛素化修饰，但无自抑制功能。

3.3.1 K48、K27连接的泛素化对MDA5的调控作用

除了前面所提到的E3泛素连接酶TRIM40、Parkin能介导MDA5的K48链泛素化外，还有一种非典型激酶Riok3募集并与TRIM40相互作用，导致MDA5和RIG-I通过K48和K27连接的泛素化降解，抑制了抗病毒信号的传导^[56]。另有研究发现，PRRSV感染细胞促进了RNF122介导的MDA5的K27/K48连接的泛素化，降解MDA5，抑制IFN的产生，最终促进病毒增殖^[57]。

3.3.2 K63连接的泛素化对MDA5的调控作用

研究发现线粒体样蛋白ERAL1在病毒感染后，通过BAX/BAK孔从线粒体释放到胞质，胞质中的ERAL1则促进MDA5和RIG-I的K63连接的泛素化，并促进下游MAVS聚集，从而激活抗病毒信号^[58]。还有研究发现TRIM65也能促进MDA5的K63连接的泛素化^[59]，从而激活MDA5来激活天然免疫。研究发现传染性支气管炎病毒(infectious bronchitis virus, IBV)编码的一种木瓜蛋白酶样蛋白酶PLpro，具有蛋白水解酶和体外去泛素酶活性，IBV PLpro在DF-1细胞中过表达时，能够促进MDA5和TBK1去除K63连接的泛素化，从而削弱抗病毒信号的传导^[39]。

3.4 泛素化修饰对MAVS的调控作用

作为RLRs信号通路的重要枢纽，MAVS通过其羧基末端TM结构域锚定在线粒体外膜蛋白上，利用CARD与RLRs相互作用^[60]，发生着各种翻译后修饰和生化反应，激活天然免疫，成为学者们研究RLRs信号通路的热点。

3.4.1 K48连接的泛素化对MAVS的调控作用

有研究发现坦布苏病毒(Tambusu virus, TMUV) NS2B能与MAVS特异性互作，促进MAVS的K48连接的泛素化和蛋白酶体途径发生降解；此外NS2B还能通过募集E3泛素连接酶MARCH5进行多泛素化修饰MAVS，从而抑制I型IFN和炎症因子的产生，达到抑制细胞的抗病毒反应^[61]。NLRX1是丙型肝炎病毒(hepatitis C virus, HCV)的一种诱导蛋白，能与MAVS相互作用并介导K48连接的多泛素化^[62]。生发中心激酶MST4促进E3泛素连接酶Smurf1和MAVS之间的相互作用，这促进了MAVS的K48泛素化启动蛋白酶体降解^[63]。BCL2相关抗凋亡基因6 (BCL2-associated athanogene 6, BAG6)也能促进K48连接的泛素化来抑制MAVS的聚集，并特异性地减弱MAVS对TRAF2的募集以抑制RLRs信号传导^[64]。此外，神经前体细胞表达发育性调控的下调蛋白4 (neuroprogenitor cells express developmentally regulated down-regulated protein4, NEDD4)结合蛋白3 (NEDD4 binding protein 3, N4BP3)和跨膜蛋白33 (transmembrane protein 33, TMEM33)也可以促进MAVS的K48连接的泛素化修饰^[65-66]；RNF114也能靶向MAVS和TRAF3进行K27和K48连接的泛素化和蛋白降解^[67]；这些能促进K48位点泛素化的物质，均能干扰抗病毒信号通路。与之相反，减数分裂重组蛋白REC8是染色体结构维持蛋白SMC的成员，在减数分裂、抗肿瘤活性和精子形成中起重要作用，Chen等的研究发现，REC8能与细胞质中的MAVS相互作用，抑制RNF5触发的MAVS的K48连接的泛素化^[68]，从而使MAVS能顺利激活下游信号分子，稳定天然免疫。

3.4.2 K63连接的泛素化对MAVS的调控作用

TRIM31能与MAVS相互作用，催化MAVS上Lys10、Lys311和Lys461的K63连接的多泛素化，激活下游分子，从而诱导I型IFN和炎症因子的产生^[69]。定位于线粒体的支架蛋白USP18能与MAVS特异性相互作用，促进K63连接的多泛素化；而USP18作为支架蛋白，能促进TRIM31的重新定位，并增强线粒体中TRIM31和MAVS之间的相互作用^[70]。另外，Chen等过表达Sec13也增加了MAVS的聚集和K63连接的泛素化，并显著增强了IRF3的磷酸化和二聚化^[71]，促进IFN-β的产生^[72]。NEDD4结合蛋白3 (N4BP3)通过靶向MAVS促进MAVS的K63连接的泛素化修饰，是RLR信号通路的正调节因子^[65]。而支架蛋白FAF1通过与TRIM31竞争MAVS来拮抗MAVS的K63连接的多泛素化和聚集，但K48连接的多泛素化却没有受到影响^[73]。

3.4.3 K27连接的泛素化对MAVS的调控作用

He等过表达RNF34发现其显著促进MAVS的K27/K29连接的泛素化^[74]。骨髓基质细胞抗原2 (bone marrow stromal cell antigen 2, BST2/ tetherin)是一种干扰素诱导的抗病毒因子，具有阻止受感染细胞释放包膜病毒的能力，研究发现tetherin能招募E3泛素连接酶MARCH8催化Lys7处MAVS上的K27连接的泛素化，作为NDP52依赖性自噬降解的识别信号^[75]。

3.5 泛素化修饰对TRAFs家族的调控作用

TRAFs是参与细胞内信号转导的重要衔接蛋白，连接着不同的信号通路，目前发现有7个家族成员。基于TRAFs结构上的TRAF结构域，使得该家族具有E3泛素连接酶功能和支架功能，而RING和ZF结构域的二聚化则是K63连接的泛素链组装所必需的。

3.5.1 泛素化修饰对TRAF2的调控作用

一种线粒体亚型脱氧尿苷三磷酸核苷水解酶DUT-M，通过与RIG-I和MAVS相互作用来推动组装MAVS-TRAF2复合物，增强TRAF2的K63链多泛素化，导致IRF3二聚化和p65磷酸化的激活增强，从而激活I型IFN和炎症因子的产生^[76]。SRY相关转录因子9 (SRY-box transcription factor 9, SOX9)与MAVS相互作用并靶向MAVS以抑制MAVS-TRAF2的关联，从而抑制MAVS介导的TRAF2的K63链泛素化，下调IFN-β表达和抗病毒信号转导^[77]。

3.5.2 泛素化修饰对TRAF3的调控作用

雌激素受体α (estrogen receptor α, ERα)是配体激活转录因子的核受体的成员，能直接与TRAF3相互作用并促进TRAF3的K48链蛋白酶体降解，抑制下游分子的激活进而抑制抗病毒反应^[78]。细胞凋亡抑制剂2 (cellular inhibitor of apoptosis 2, cIAP2)通过与禽流感病毒H7N9 NP蛋白竞争性结合TRAF3来稳定TRAF3表达，从而抑制K48连接的多泛素化和TRAF3的降解^[79]。PINK1则通过激酶结构域与TRAF3结合，并抑制Parkin介导的TRAF3 K48链的泛素化和蛋白酶体降解，从而使得抗病毒免疫反应顺利进行^[80]。

RNF166则通过增强TRAF3和TRAF6的K63链的泛素化调节RNA病毒触发的IFN-β的产生^[81]。TRIM24也能促进TRAF3 K63连接的泛素化，使其与MAVS和TBK1相关联，从而激活下游抗病毒信号^[82]。Forkhead转录因子1 (forkhead box O1, FoxO1)是一种宿主转录因子，在SeV感染后，FoxO1抑制了TRAF3 K63链的泛素化以及与TBK1之间的互作，从而干扰IRF3途径减少I型干扰素的产生^[83]。

3.5.3 泛素化修饰对TRAF6的调控作用

由牛疱疹病毒Ⅰ型(bovine herpesvirus 1, BHV-1)编码的早期蛋白BICP0具有E3泛素连接酶活性，能通过泛素蛋白酶体系统促进TRAF6的K48泛素化和降解^[84]。NLRP11是NLRs家族的成员，能通过依赖MAVS的方式增强TRAF6的K48连接的泛素化而诱导TRAF6降解^[62]。肠道病毒71 (enterovirus 71, EV71)感染宿主细胞后，在体外和体内减弱了去泛素化酶USP4的表达，而USP4可通过去除TRAF6的K48连接的泛素化降低TRAF6的降解，以此显著抑制了EV71的复制^[85]。

泛素样蛋白UBL4A能促进TRAF6的K63连接的泛素化，上调I型干扰素的产生^[86]。半乳糖凝集素3结合蛋白(galectin 3 binding protein, LGALS3BP)作为支架蛋白与TRAF6、TRAF3相互作用增强TRAF6和TRAF3 K63连接的泛素化，并作为TRAF6的特异性泛素化底物，诱导I型IFN和促炎细胞因子的产生来抑制病毒复制^[87]。LGP2则通过与泛素连接酶E2N (ubiquitin conjugating enzyme E2N, UBE2N)的结合以此抑制TRAF6的K63链的泛素化^[88]。

3.6 泛素化修饰对TBK1的调控作用

TBK1在信号通路中主要是激活下游IRFs家族，促进I型IFN的产生，而THOC7能增加TBK1的K48多泛素化使其降解，负调节I型IFN的产生^[89]。丝裂原活化的蛋白激酶1 (mitogen-activated protein kinase 1, MAP4K1)通过泛素连接酶DTX4促进K48连接的泛素化对TBK1/IKKε进行降解^[90]。除此之外，GCRV通过保留TBK1的K63连接的泛素化促进K48连接的泛素化来抑制TBK1活化，阻断IFN反应，进而实现免疫逃避^[91]。Parkin通过促进TBK1的K63连接多泛素化，促进线粒体自噬，有效地挽救心脏衰老^[92]。另外在EV71感染细胞后会上调USP24的表达，降低TBK1的K63连接的多泛素化，进一步增强EV71感染^[93]。RNF144B通过IBR结构域与TBK1的SDD结构域互作，也可抑制TBK1的K63链多泛素化，导致TBK1失活^[94]。最新研究还发现，鱼类病原体神经坏死病毒(nervous necrosis virus, NNV)招募了RNF34，通过促进K27和K48连接的TBK1和IRF3泛素化和降解，抑制RLR介导的IFN反应^[95]。

3.7 泛素化修饰对IRFs的调控作用

IRFs是抗病毒免疫信号通路中重要的转录因子之一，目前已发现有9个家族成员。在RLRs信号通路中，IRFs发生磷酸化而激活，对于调节I型IFN的产生至关重要^[96]。

3.7.1 泛素化修饰对IRF3的调控作用

对IRF3的泛素化研究大多集中于K48位点，如FoxO1通过促进TRIM21或TRIM22介导的IRF3 K48的泛素化来破坏IRF3的稳定性^[83]。另一种E3泛素连接酶MID1也与IRF3结合，促进其K48位点的多泛素化^[97]。含Jumonji结构域蛋白6 (Jumonji domain containing 6, JMJD6)通过募集RNF5来促进IRF3 K48连接的泛素化，负向调控I型干扰素的产生^[98]。此外，伪狂犬病病毒(pseudorabies virus, PRV)蛋白激酶UL13也通过靶向IRF3进行K48链的泛素化抑制IFN-β信号通路^[99]。过表达斑马鱼的含卵巢肿瘤结构域(ovarian tumor domain, OTU)的去泛素化酶6B (OTU deubiquitinase 6B, OTUD6B)能抑制TRAF6介导的K63连接的IRF3/IRF7泛素化，另外还削弱了TBK1与IRF3和IRF7的结合，导致两者的磷酸化受损^[100]。斑马鱼F-box蛋白3 (F-box protein 3, FBXO3)却促进IRF3/7的K27连接的多泛素化负调控抗病毒反应^[101]。去泛素酶PSMD14/POH1通过切割IRF3上Lys313处连接的K27多泛素链来维持IRF3的基础水平和IRF3介导的I型干扰素的活化，从而防止IRF3自噬降解^[102]。LUBAC是一种线性多泛素化酶复合物，可对IRF3的2个赖氨酸残基进行M1连接的多泛素化修饰^[103]。Raja等的最新研究发现，去泛素酶Otulin能通过去除LUBAC对IRF3 M1连接的多泛素化来抑制RIG-I诱导的细胞凋亡途径^[104]。

3.7.2 泛素化修饰对IRF7的调控作用

研究发现斑马鱼RPZ5蛋白在TBK1激活下通过K48连接的泛素化降解磷酸化的IRF7，促进病毒增殖^[105]。N-myc下游调节基因1a (N-myc downstream regulated 1, NDRG1a)和GCRV VP56也能与IRF7相互作用，促进IRF7 K48位点的泛素化，负向调节抗病毒反应^[106-107]。最新研究还发现X连锁凋亡抑制蛋白相关因子1 (X-linked apoptosis inhibitory protein correlation factor 1, XAF1)能特异性与IRF7作用，即通过控制E3泛素连接酶复合物BTB-CUL3-RBX1，使其直接靶向IRF7并促进K48连接的泛素化^[108]。而在建立PD小鼠模型中，发现去泛素化酶OTUB1能去除IRF7 K48连接的泛素化，增强IRF7的稳定性，从而促进PD小鼠的氧化应激损伤和炎症反应^[109]。而IRF7还能与神经化的E3泛素蛋白连接酶3 (neuralized E3 ubiquitin protein ligase 3, NEURL3)相互作用，触发IRF7 Lys375上的K63位点的多泛素化，增强抗病毒免疫反应^[110]。TAR RNA结合蛋白2 (TAR RNA binding protein 2, TARBP2)则会抑制TRAF6介导的K63连接的IRF7泛素化^[111]。

3.8 泛素化修饰对其他分子的调控作用

Li等证明含与人乳头瘤病毒E6相关蛋白(human papilloma virus E6 related protein, E6AP) C端同源(homologous to E6AP C terminus, HECT)结构域的E3泛素连接酶3 (HECT domain E3 ubiquitin protein ligase 3, HECTD3)通过在K296位点经K27和K63连接的多聚泛素链泛素化IKKα，增强IKKα的稳定性、核定位和激酶活性，从而促进NF-κB靶基因转录、启动I型干扰素的产生^[112]；以及TRIM22不仅可结合IκBα并诱导K48连接的泛素化加速其降解，启动抗病毒信号，还可与NEMO形成复合物并促进K63连接的泛素化，导致IKKα/β和IκBα磷酸化，从而激活抗病毒反应^[113]。

4 展望

收起

大部分RNA病毒可通过靶向促进RLRs信号通路中关键效应器分子的K48连接的泛素化，以此破坏RLRs信号通路的信号传导，逃逸宿主抗病毒免疫，实现自身的增殖。抑或是通过抑制RLRs信号通路上靶蛋白的K63等位点的泛素化，使得靶蛋白的激活受到抑制而无法进行胞内信号的传导，亦同样达到天然免疫失效的目的。由此类比，宿主的某些细胞因子、泛素特异性酶类同样按此方式调控信号通路上的泛素化修饰来遏制病毒的入侵或调节免疫障碍导致的自身免疫性疾病，这也为相关疾病的研究提供更多的治疗靶点。本课题组主要聚焦EMCV与宿主细胞蛋白互作机制研究，已发现EMCV的结构蛋白VP2通过其C端与MDA5、MAVS、TBK1和IRF3相互作用，促进蛋白泛素化，通过蛋白酶体和溶酶体途径显著降解RLRs，首证EMCV利用其VP2逃避宿主的抗病毒反应。筛选出HSP90、DDX56、膜联蛋白A2等调控病毒感染机制等宿主细胞蛋白，为进一步研究病毒感染机制奠定基础^[114]。

此外，在RLRs中已发现许多能导致RIG-I和MDA5发生泛素化修饰的物质，但关于LGP2的泛素化及其功能的研究却不多。最初发现TRIM14能使RIG-I发生泛素化，但后来发现LGP2能被TRIM14通过二价PSpry和Hel2表位直接特异性识别和结合，而不与RIG-I结合^[50]，可推断TRIM14与RIG-I的泛素化修饰功能可能是通过其与LGP2的相互作用间接介导。这也为关于LGP2其他功能的研究以及拓展更多RLRs信号通路上其他翻译后修饰提供思路，亦是今后完善RLRs家族生理功能研究的思路之一。

目前对单链泛素化修饰作用积淀了一些研究基础，但对多聚泛素链修饰、混合多泛素链、线性多泛素链等方面的研究仍然知之甚微，这些泛素链修饰所造成底物蛋白性质的改变也是拓展对泛素化修饰的研究重点之一。迄今为止对信号通路泛素化修饰的研究主要是为寻找用以抑制病毒复制或增强免疫信号的新靶点，本文通过对RLRs信号通路关键因子的泛素化调控作用深入概括与分析，以期为寻找新的治疗RNA病毒感染引起的疾病或自身免疫性疾病的靶点提供策略和方法。

基金

收起

西北民族大学中央高校基本科研业务费资金(31920230163)
西北民族大学中央高校基本科研业务费资金(31920230162)
国家自然科学基金(32260037)
科学技术部“高端外国专家引进计划”(G2022187005L)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

KUMAR H, KAWAI T, AKIRA S.Pathogen recognition by the innate immune system[J].International Reviews of Immunology,2011,30(1):16-34.

https://doi.org/10.3109/08830185.2010.529976

[2]

NAKHAEI P, GENIN P, CIVAS A, HISCOTT J.RIG-I-like receptors: sensing and responding to RNA virus infection[J].Seminars in Immunology,2009,21(4):215-222.

https://doi.org/10.1016/j.smim.2009.05.001

[3]

LOO YM, GALE MJ.Immune signaling by RIG-I-like receptors[J].Immunity,2011,34(5):680-692.

https://doi.org/10.1016/j.immuni.2011.05.003

[4]

NAKAMURA N.Ubiquitin system[J].International Journal of Molecular Sciences,2018,19(4):1080.

https://doi.org/10.3390/ijms19041080

[5]

REHWINKEL J, GACK MU.RIG-I-like receptors: their regulation and roles in RNA sensing[J].Nature Reviews Immunology,2020,20(9):537-551.

https://doi.org/10.1038/s41577-020-0288-3

[6]

BRISSE M, LY H.Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5[J].Frontiers in Immunology,2019,10:1586.

https://doi.org/10.3389/fimmu.2019.01586

[7]

THORESEN D, WANG WS, GALLS D, GUO R, XU L, PYLE AM.The molecular mechanism of RIG-I activation and signaling[J].Immunological Reviews,2021,304(1):154-168.

https://doi.org/10.1111/imr.13022

[8]

BAI XM, SUI C, LIU F, CHEN T, ZHANG L, ZHENG Y, LIU BY, GAO CJ.The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation[J].Nature Communications,2022,13:5016.

https://doi.org/10.1038/s41467-022-32628-y

[9]

DAS A, MIDDLETON AJ, PADALA P, LEDGERWOOD EC, MACE PD, DAY CL.The structure and ubiquitin binding properties of TRAF RING heterodimers[J].Journal of Molecular Biology,2021,433(8):166844.

https://doi.org/10.1016/j.jmb.2021.166844

[10]

XU GZ, LO YC, LI QB, NAPOLITANO G, WU XF, JIANG XL, DREANO M, KARIN M, WU H.Crystal structure of inhibitor of κB kinase β[J].Nature,2011,472(7343):325-330.

https://doi.org/10.1038/nature09853

[11]

YANAI H, NEGISHI H, TANIGUCHI T.The IRF family of transcription factors[J].OncoImmunology,2012,1(8):1376-1386.

https://doi.org/10.4161/onci.22475

[12]

PAUL A, TANG TH, NG SK.Interferon regulatory factor 9 structure and regulation[J].Frontiers in Immunology,2018,9:1831.

https://doi.org/10.3389/fimmu.2018.01831

[13]

NAPETSCHNIG J, WU H.Molecular basis of NF-κB signaling[J].Annual Review of Biophysics,2013,42:443-468.

https://doi.org/10.1146/annurev-biophys-083012-130338

[14]

TAM WF, SEN R.IκB family members function by different mechanisms[J].Journal of Biological Chemistry,2001,276(11):7701-7704.

https://doi.org/10.1074/jbc.C000916200

[15]

GOLDSTEIN G, SCHEID M, HAMMERLING U, SCHLESINGER DH, NIALL HD, BOYSE EA.Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells[J].Proceedings of the National Academy of Sciences of the United States of America,1975,72(1):11-15.

[16]

SWATEK KN, USHER JL, KUECK AF, GLADKOVA C, MEVISSEN TET, PRUNEDA JN, SKERN T, KOMANDER D.Insights into ubiquitin chain architecture using Ub-clipping[J].Nature,2019,572(7770):533-537.

https://doi.org/10.1038/s41586-019-1482-y

[17]

GRICE GL, NATHAN JA.The recognition of ubiquitinated proteins by the proteasome[J].Cellular and Molecular Life Sciences,2016,73(18):3497-3506.

https://doi.org/10.1007/s00018-016-2255-5

[18]

MORIMOTO D, SHIRAKAWA M.The evolving world of ubiquitin: transformed polyubiquitin chains[J].Biomolecular Concepts,2016,7(3):157-167.

https://doi.org/10.1515/bmc-2016-0009

[19]

SWATEK KN, KOMANDER D.Ubiquitin modifications[J].Cell Research,2016,26(4):399-422.

https://doi.org/10.1038/cr.2016.39

[20]

AALTO A, MARTÍNEZ-CHACÓN G, KIETZ C, TSYGANOVA N, KREUTZER J, KALLIO P, BROEMER M, MEINANDER A.M1-linked ubiquitination facilitates NF-κB activation and survival during sterile inflammation[J].The FEBS Journal,2022,289(17):5180-5197.

https://doi.org/10.1111/febs.16425

[21]

GREENFELD H, TAKASAKI K, WALSH MJ, ERSING I, BERNHARDT K, MA YJ, FU BS, ASHBAUGH CW, CABO J, MOLLO SB, ZHOU HF, LI ST, GEWURZ BE.TRAF1 coordinates polyubiquitin signaling to enhance Epstein-Barr virus LMP1-mediated growth and survival pathway activation[J].PLoS Pathogens,2015,11(5):e1004890.

https://doi.org/10.1371/journal.ppat.1004890

[22]

DURCAN TM, TANG MY, PÉRUSSE JR, DASHTI EA, AGUILETA MA, McLELLAND GL, GROS P, SHALER TA, FAUBERT D, COULOMBE B, FON EA.USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin[J].The EMBO Journal,2014,33(21):2473-2491.

https://doi.org/10.15252/embj.201489729

[23]

ELIA AEH, BOARDMAN AP, WANG DC, HUTTLIN EL, EVERLEY RA, DEPHOURE N, ZHOU CS, KOREN I, GYGI SP, ELLEDGE SJ.Quantitative proteomic atlas of ubiquitination and acetylation in the DNA damage response[J].Molecular Cell,2015,59(5):867-881.

https://doi.org/10.1016/j.molcel.2015.05.006

[24]

LI JK, WANG N, MA JJ, CHENG YQ, WANG HG, SUN JH, YAN YX.Porcine deltacoronavirus nucleocapsid protein species-specifically suppressed IRF7-induced type Ⅰ interferon productionvia ubiquitin-proteasomal degradation pathway[J].Veterinary Microbiology,2020,250:108853.

https://doi.org/10.1016/j.vetmic.2020.108853

[25]

MATSUMOTO ML, WICKLIFFE KE, DONG KC, YU C, BOSANAC I, BUSTOS D, PHU L, KIRKPATRICK DS, HYMOWITZ SG, RAPE M, KELLEY RF, DIXIT VM.K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody[J].Molecular Cell,2010,39(3):477-484.

https://doi.org/10.1016/j.molcel.2010.07.001

[26]

ZHENG YY, LIU QX, WU YX, MA L, ZHANG ZZ, LIU T, JIN SH, SHE YC, LI YP, CUI J.Zika virus elicits inflammation to evade antiviral response by cleaving cGASvia NS1-caspase-1 axis[J].The EMBO Journal,2018,37(18):e99347.

https://doi.org/10.15252/embj.201899347

[27]

GATTI M, PINATO S, MAIOLICA A, ROCCHIO F, PRATO MG, AEBERSOLD R, PENENGO L.RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage[J].Cell Reports,2015,10(2):226-238.

https://doi.org/10.1016/j.celrep.2014.12.021

[28]

ZHOU QQ, ZHANG J.K27-linked noncanonic ubiquitination in immune regulation[J].Journal of Leukocyte Biology,2022,111(1):223-235.

[29]

MA ZC, BAI J, JIANG CL, ZHU HX, LIU DP, PAN MJ, WANG XW, PI J, JIANG P, LIU X.Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy[J].Autophagy,2023,19(5):1512-1532.

https://doi.org/10.1080/15548627.2022.2139921

[30]

SINGH R, KARRI D, SHEN H, SHAO JY, DASGUPTA S, HUANG SX, EDWARDS DP, ITTMANN MM, O'MALLEY BW, YI P.TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis[J].Journal of Clinical Investigation,2018,128(7):3129-3143.

https://doi.org/10.1172/JCI96060

[31]

KONG ZJ, YIN HY, WANG F, LIU Z, LUAN XH, SUN L, LIU WJ, SHANG YL.Pseudorabies virus tegument protein UL13 recruits RNF5 to inhibit STING-mediated antiviral immunity[J].PLoS Pathogens,2022,18(5):e1010544.

https://doi.org/10.1371/journal.ppat.1010544

[32]

YANG MJ, CHEN TY, LI XL, YU Z, TANG SQ, WANG C, GU Y, LIU YF, XU S, LI WH, ZHANG XM, WANG JL, CAO XT.K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation[J].Nature Immunology,2015,16(12):1253-1262.

https://doi.org/10.1038/ni.3258

[33]

DENG TJ, HU BL, WANG XB, LIN LL, ZHOU JW, XU YT, YAN Y, ZHENG XJ, ZHOU JY.Inhibition of antiviral innate immunity by Avibirnavirus VP3via blocking TBK1-TRAF3 complex formation and IRF3 activation[J].mSystems,2021,6(3):e00016-21.

[34]

WEERAWARDHANA A, UDDIN MB, CHOI JH, PATHINAYAKE P, SHIN SH, CHATHURANGA K, PARK JH, LEE JS.Foot-and-mouth disease virus non-structural protein 2B downregulates the RLR signaling pathwayvia degradation of RIG-I and MDA5[J].Frontiers in Immunology,2022,13:1020262.

https://doi.org/10.3389/fimmu.2022.1020262

[35]

SU H, FAN CJ, LIAO ZW, YANG CR, CLARKE JL, ZHANG YA, SU JG.Grass carp reovirus major outer capsid protein VP4 interacts with RNA sensor RIG-I to suppress interferon response[J].Biomolecules,2020,10(4):560.

https://doi.org/10.3390/biom10040560

[36]

JIN YL, JIA KT, ZHANG WW, XIANG YX, JIA P, LIU W, YI MS.Zebrafish TRIM25 promotes innate immune response to RGNNV infection by targeting 2CARD and RD regions of RIG-I for K63-linked ubiquitination[J].Frontiers in Immunology,2019,10:2805.

https://doi.org/10.3389/fimmu.2019.02805

[37]

KAMSTEEG EJ, HENDRIKS G, BOONE M, KONINGS IBM, OORSCHOT V, van der SLUIJS P, KLUMPERMAN J, DEEN PMT.Short-chain ubiquitination mediates the regulated endocytosis of the aquaporin-2 water channel[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103(48):18344-18349.

[38]

ZHI HJ, GUO X, HO YK, PASUPALA N, ALEXANDER ANDERS ENGSTROM H, SEMMES OJ, GIAM CZ.RNF8 dysregulation and down-regulation during HTLV-1 infection promote genomic instability in adult T-cell leukemia[J].PLoS Pathogens,2020,16(5):e1008618.

https://doi.org/10.1371/journal.ppat.1008618

[39]

OJHA NK, LIU JJ, YU TQ, FANG CX, ZHOU JY, LIAO M.Interplay of the ubiquitin proteasome system and the innate immune response is essential for the replication of infectious bronchitis virus[J].Archives of Virology,2021,166(8):2173-2185.

https://doi.org/10.1007/s00705-021-05073-3

[40]

RAASI S, PICKART CM.Ubiquitin chain synthesis[J].Methods in Molecular Biology (Clifton, NJ),2005,301:47-55.

[41]

STOK JE, OOSENBRUG T, TER HAAR LR, GRAVEKAMP D, BROMLEY CP, ZELENAY S, REIS E SOUSA C, van der VEEN AG.RNA sensingvia the RIG-I-like receptor LGP2 is essential for the induction of a type Ⅰ IFN response in ADAR1 deficiency[J].The EMBO Journal,2022,41(6):e109760.

https://doi.org/10.15252/embj.2021109760

[42]

RAO YL, WAN QY, YANG CR, SU JG.Grass carp laboratory of genetics and physiology 2 serves as a negative regulator in retinoic acid-inducible gene I- and melanoma differentiation-associated gene 5-mediated antiviral signaling in resting state and early stage of grass carp reovirus infection[J].Frontiers in Immunology,2017,8:352.

[43]

KOUWAKI T, NISHIMURA T, WANG GM, NAKAGAWA R, OSHIUMI H.K63-linked polyubiquitination of LGP2 by Riplet regulates RIG-I-dependent innate immune response[J].EMBO Reports,2023,24(2):e54844.

https://doi.org/10.15252/embr.202254844

[44]

ZHU ZB, ZHANG M, YUAN LL, XU YQ, ZHOU H, LIAN ZM, LIU PR, LI XD.LGP2 promotes type Ⅰ interferon production to inhibit PRRSV infectionvia enhancing MDA5-mediated signaling[J].Journal of Virology,2023,97(1):e0184322.

https://doi.org/10.1128/jvi.01843-22

[45]

ZHAO CY, JIA MT, SONG H, YU ZX, WANG WW, LI Q, ZHANG LN, ZHAO W, CAO XT.The E3 ubiquitin ligase TRIM40 attenuates antiviral immune responses by targeting MDA5 and RIG-I[J].Cell Reports,2017,21(6):1613-1623.

https://doi.org/10.1016/j.celrep.2017.10.020

[46]

YANG YX, HUANG JP, LI SN, LI J, LING T, XIE T, XU LG.HSPBP1 facilitates cellular RLR-mediated antiviral response by inhibiting the K48-linked ubiquitination of RIG-I[J].Molecular Immunology,2021,134:62-71.

https://doi.org/10.1016/j.molimm.2021.03.002

[47]

LI J, CHEN T, XIE T, YANG YX, HE TS, XU LG.SNX5 inhibits RLR-mediated antiviral signaling by targeting RIG-I-VISA signalosome[J].Biochemical and Biophysical Research Communications,2020,522(4):889-896.

https://doi.org/10.1016/j.bbrc.2019.11.121

[48]

XU SS, XU LG, YUAN CL, LI SN, CHEN T, WANG WY, LI CS, CAO LZ, RAO H.FKBP8 inhibits virus-induced RLR-VISA signaling[J].Journal of Medical Virology,2019,91(3):482-492.

https://doi.org/10.1002/jmv.25327

[49]

PARK YJ, OANH NTK, HEO J, KIM SG, LEE HS, LEE H, LEE JH, KANG HC, LIM W, YOO YS, CHO H.Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity[J].Cellular Signalling,2020,67:109520.

https://doi.org/10.1016/j.cellsig.2019.109520

[50]

LI DY, WANG HY, ZHANG PP, ZHANG YH, HE X, ZHONG H, GUAN K, MIN M, GAO Q, WEI CW.Yersinia YopT inhibits RLH-mediated NF-κB and IRF3 signal transduction[J].Microbiology and Immunology,2020,64(11):768-777.

https://doi.org/10.1111/1348-0421.12842

[51]

LIAN H, ZANG R, WEI J, YE W, HU MM, CHEN YD, ZHANG XN, GUO Y, LEI CQ, YANG Q, LUO WW, LI S, SHU HB.The zinc-finger protein ZCCHC3 binds RNA and facilitates viral RNA sensing and activation of the RIG-I-like receptors[J].Immunity,2018,49(3):438-448.e5.

https://doi.org/10.1016/j.immuni.2018.08.014

[52]

YANG ZW, WANG J, HE BL, ZHANG XL, LI XJ, KUANG ES.Correction: RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination[J].eLife,2021,10:68958.

https://doi.org/10.7554/eLife.68958

[53]

RAN XH, ZHU JW, CHEN YY, NI RZ, MU D.Papain-like protease of SARS-CoV-2 inhibits RLR signaling in a deubiquitination-dependent and deubiquitination-independent manner[J].Frontiers in Immunology,2022,13:947272.

https://doi.org/10.3389/fimmu.2022.947272

[54]

JI LK, LI SS, ZHU WX, MA JJ, SUN JH, WANG HG, YAN YX.Porcine deltacoronavirus nucleocapsid protein suppressed IFN-β production by interfering porcine RIG-I dsRNA-binding and K63-linked polyubiquitination[J].Frontiers in Immunology,2019,10:1024.

https://doi.org/10.3389/fimmu.2019.01024

[55]

LIU Y, LIANG QZ, LU W, YANG YL, CHEN RA, HUANG YW, WANG B.A comparative analysis of coronavirus nucleocapsid (N) proteins reveals the SADS-CoV N protein antagonizes IFN-β production by inducing ubiquitination of RIG-I[J].Frontiers in Immunology,2021,12:688758.

https://doi.org/10.3389/fimmu.2021.688758

[56]

SHEN Y, TANG KJ, CHEN DD, HONG MY, SUN FF, WANG SS, KE YH, WU TT, SUN R, QIAN J, DU YS.Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation[J].Cell Reports,2021,35(12):109272.

https://doi.org/10.1016/j.celrep.2021.109272

[57]

SUN RQ, GUO YY, LI XY, LI RQ, SHI JX, TAN Z, ZHANG LL, ZHANG L, HAN J, HUANG JH.PRRSV non-structural proteins orchestrate porcine E3 ubiquitin ligase RNF122 to promote PRRSV proliferation[J].Viruses,2022,14(2):424.

https://doi.org/10.3390/v14020424

[58]

LI SJ, KUANG M, CHEN LY, LI YF, LIU SD, DU HQ, CAO LL, YOU FP.The mitochondrial protein ERAL1 suppresses RNA virus infection by facilitating RIG-I-like receptor signaling[J].Cell Reports,2021,34(3):108631.

https://doi.org/10.1016/j.celrep.2020.108631

[59]

KATO K, AHMAD S, ZHU ZX, YOUNG JM, MU X, PARK S, MALIK HS, HUR S.Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases[J].Molecular Cell,2021,81(3):599-613.e8.

https://doi.org/10.1016/j.molcel.2020.11.047

[60]

YASUKAWA K, KOSHIBA T.Mitochondrial reactive zones in antiviral innate immunity[J].Biochimica et Biophysica Acta (BBA)-General Subjects,2021,1865(3):129839.

https://doi.org/10.1016/j.bbagen.2020.129839

[61]

ZHOU P, LI YQ, LIU AX, ZHANG QX, WU WR, JIN H, JONGKAEWWATTANA A, HE QG, LUO R.Tembusu virus nonstructural protein 2B antagonizes type Ⅰ interferon production by targeting MAVS for degradation[J].Journal of Virology,2022,96(14):e0081622.

https://doi.org/10.1128/jvi.00816-22

[62]

QIN YF, SU ZX, WU YX, WU CL, JIN SH, XIE WH, JIANG W, ZHOU RB, CUI J.NLRP 11 disrupts MAVS signalosome to inhibit type Ⅰ interferon signaling and virus-induced apoptosis[J].EMBO Reports,2017,18(12):2160-2171.

https://doi.org/10.15252/embr.201744480

[63]

LIU W, MA ZL, WU YR, YUAN C, ZHANG YY, LIANG ZY, YANG Y, ZHANG WW, JIAO PT.MST4 negatively regulates type Ⅰ interferons productionvia targeting MAVS-mediated pathway[J].Cell Communication and Signaling,2022,20(1):1-16.

https://doi.org/10.1186/s12964-021-00806-y

[64]

HUANG JP, LI J, XIAO YP, XU LG.BAG6 negatively regulates the RLR signaling pathway by targeting VISA/MAVS[J].Frontiers in Immunology,2022,13:972184.

https://doi.org/10.3389/fimmu.2022.972184

[65]

WANG C, LING T, ZHONG N, XU LG.N4BP3 regulates RIG-I-like receptor antiviral signaling positively by targeting mitochondrial antiviral signaling protein[J].Frontiers in Microbiology,2021,12:770600.

https://doi.org/10.3389/fmicb.2021.770600

[66]

LU LF, ZHANG C, LI ZC, ZHOU XY, JIANG JY, CHEN DD, ZHANG YA, XIONG F, ZHOU F, LI S.A novel role of zebrafish TMEM33 in negative regulation of interferon production by two distinct mechanisms[J].PLoS Pathogens,2021,17(2):e1009317.

https://doi.org/10.1371/journal.ppat.1009317

[67]

XIANG YX, ZHANG WW, JIA P, LU XB, LIU W, YI MS, JIA KT.E3 ubiquitin ligase RNF114 inhibits innate immune response to red-spotted grouper nervous necrosis virus infection in sea perch by targeting MAVS and TRAF3 to mediate their degradation[J].The Journal of Immunology,2021,206(1):77-88.

https://doi.org/10.4049/jimmunol.2000083

[68]

CHEN SW, LIU Q, ZHANG L, MA JH, XUE BB, LI HY, DENG RL, GUO MM, XU Y, TIAN RY, WANG JJ, CAO WY, YANG Q, WANG LL, LI XR, LIU S, YANG D, ZHU HZ.The role of REC8 in the innate immune response to viral infection[J].Journal of Virology,2022,96(6):e0217521.

https://doi.org/10.1128/jvi.02175-21

[69]

LIU BY, ZHANG M, CHU HL, ZHANG HH, WU HF, SONG GH, WANG P, ZHAO K, HOU JX, WANG XE, ZHANG L, GAO CJ.The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination[J].Nature Immunology,2017,18(2):214-224.

https://doi.org/10.1038/ni.3641

[70]

HOU JX, HAN LL, ZHAO Z, LIU HQ, ZHANG L, MA CH, YI F, LIU BY, ZHENG Y, GAO CJ.USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS[J].Nature Communications,2021,12(1):2970.

https://doi.org/10.1038/s41467-021-23219-4

[71]

CHEN T, WANG DD, XIE T, XU LG.Sec13 is a positive regulator of VISA-mediated antiviral signaling[J].Virus Genes,2018,54(4):514-526.

https://doi.org/10.1007/s11262-018-1581-0

[72]

SO T.The immunological significance of tumor necrosis factor receptor-associated factors (TRAFs)[J].International Immunology,2022,34(1):7-20.

https://doi.org/10.1093/intimm/dxab058

[73]

DAI T, WU LM, WANG S, WANG J, XIE F, ZHANG ZK, FANG XW, LI JX, FANG PF, LI F, JIN K, DAI JF, YANG B, ZHOU FF, van DAM H, CAI DC, HUANG HZ, ZHANG L.FAF1 regulates antiviral immunity by inhibiting MAVS but is antagonized by phosphorylation upon viral infection[J].Cell Host & Microbe,2018,24(6):776-790.e5.

[74]

HE X, ZHU YJ, ZHANG YH, GENG YQ, GONG J, GENG J, ZHANG PP, ZHANG XT, LIU N, PENG YM, WANG CB, WANG YJ, LIU X, WAN LM, GONG F, WEI CW, ZHONG H.RNF34 functions in immunity and selective mitophagy by targeting MAVS for autophagic degradation[J].The EMBO Journal,2019,38(14):e100978.

https://doi.org/10.15252/embj.2018100978

[75]

JIN SH, TIAN S, LUO M, XIE WH, LIU T, DUAN TH, WU YX, CUI J.Tetherin suppresses type Ⅰ interferon signaling by targeting MAVS for NDP52-mediated selective autophagic degradation in human cells[J].Molecular Cell,2017,68(2):308-322.e4.

https://doi.org/10.1016/j.molcel.2017.09.005

[76]

WENG GX, LING T, HOU W, LI SN, CHEN T, ZHANG Z, WANG DD, XU LG.Mitochondrial DUT-M potentiates RLR-mediated antiviral signaling by enhancing VISA and TRAF2 association[J].Molecular Immunology,2021,132:117-125.

https://doi.org/10.1016/j.molimm.2021.01.023

[77]

JIANG X, XU LG.SOX9 negatively regulates the RLR antiviral signaling by targeting MAVS[J].Virus Genes,2022,58(2):122-132.

https://doi.org/10.1007/s11262-022-01886-9

[78]

WANG CX, HUANG Y, SHENG JZ, HUANG HF, ZHOU J.Estrogen receptor alpha inhibits RLR-mediated immune responsevia ubiquitinating TRAF3[J].Cellular Signalling,2015,27(10):1977-1983.

https://doi.org/10.1016/j.cellsig.2015.07.008

[79]

WEI YL, ZENG Y, ZHANG XG, XU S, WANG ZX, DU YY, ZHANG B, LEI CQ, ZHU QY.The nucleoprotein of H7N9 influenza virus positively regulates TRAF3-mediated innate signaling and attenuates viral virulence in mice[J].Journal of Virology,2020,94(24):e01640-20.

[80]

ZHOU J, YANG R, ZHANG ZR, LIU QR, ZHANG YY, WANG QQ, YUAN HB.Mitochondrial protein PINK1 positively regulates RLR signaling[J].Frontiers in Immunology,2019,10:1069.

https://doi.org/10.3389/fimmu.2019.01069

[81]

CHEN HW, YANG YK, XU H, YANG WW, ZHAI ZH, CHEN DY.Ring finger protein 166 potentiates RNA virus-induced interferon-β productionvia enhancing the ubiquitination of TRAF3 and TRAF6[J].Scientific Reports,2015,5:14770.

https://doi.org/10.1038/srep14770

[82]

ZHU QC, YU T, GAN SC, WANG Y, PEI YF, ZHAO QF, PEI SY, HAO SM, YUAN J, XU J, HOU FJ, WU XF, PENG C, WU P, QIN J, XIAO YC.TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination[J].The Journal of Experimental Medicine,2020,217(7):e20192083.

https://doi.org/10.1084/jem.20192083

[83]

MA ZL, ZHANG WW, FAN WH, WU YR, ZHANG MH, XU J, LI WQ, SUN L, LIU WJ, LIU W.Forkhead box O1-mediated ubiquitination suppresses RIG-I-mediated antiviral immune responses[J].International Immunopharmacology,2021,90:107152.

https://doi.org/10.1016/j.intimp.2020.107152

[84]

CAO C, AN R, YU YY, DAI HY, QU ZH, GAO MC, WANG JW.BICP0 negatively regulates TRAF6-mediated NF-κB and interferon activation by promoting K48-linked polyubiquitination of TRAF6[J].Frontiers in Microbiology,2020,10:3040.

https://doi.org/10.3389/fmicb.2019.03040

[85]

XU C, PENG Y, ZHANG Q, XU XP, KONG XM, SHI WF.USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication[J].Scientific Reports,2018,8(1):13418.

https://doi.org/10.1038/s41598-018-31734-6

[86]

PENG SJ, YAO RR, YU SS, CHEN HY, PANG XW, ZHANG Y, ZHANG J.UBL4A augments innate immunity by promoting the K63-linked ubiquitination of TRAF6[J].The Journal of Immunology,2019,203(7):1943-1951.

https://doi.org/10.4049/jimmunol.1800750

[87]

XU G, XIA ZC, DENG FY, LIU L, WANG QM, YU Y, WANG FB, ZHU CL, LIU WY, CHENG ZK, ZHU Y, ZHOU L, ZHANG Y, LU MJ, LIU S.Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex[J].PLoS Pathogens,2019,15(8):e1008002.

https://doi.org/10.1371/journal.ppat.1008002

[88]

JESSICA J LENOIR, JEAN-PATRICK PARISIEN, CURT M HORVATH.Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation[J].Cell Reports,2021,37(13):110175.

https://doi.org/10.1016/j.celrep.2021.110175

[89]

HE TS, XIE T, LI J, YANG YX, LI CS, WANG WY, CAO LZ, RAO H, JU C, XU LG.THO complex subunit 7 homolog negatively regulates cellular antiviral response against RNA viruses by targeting TBK1[J].Viruses,2019,11(2):158.

https://doi.org/10.3390/v11020158

[90]

HE TS, HUANG JP, CHEN T, ZHANG Z, CAI KT, YU JG, XU LG.The kinase MAP4K1 inhibits cytosolic RNA-induced antiviral signaling by promoting proteasomal degradation of TBK1/IKKε[J].Microbiology Spectrum,2021,9(3):e0145821.

https://doi.org/10.1128/Spectrum.01458-21

[91]

RAO YL, JI JF, LIAO ZW, SU H, SU JG.GCRV hijacks TBK1 to evade IRF7-mediated antiviral immune responses in grass carpCtenopharyngodon idella[J].Fish & Shellfish Immunology,2019,93:492-499.

https://doi.org/10.11964/jfc.20171111054

[92]

GAO BL, YU WJ, LV P, LIANG XY, SUN SQ, ZHANG YM.Parkin overexpression alleviates cardiac aging through facilitating K63-polyubiquitination of TBK1 to facilitate mitophagy[J].Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease,2021,1867(1):165997.

[93]

ZANG LC, GU J, YANG XY, YUAN YK, GUO H, ZHOU W, MA JH, CHEN Y, WU YM, ZHENG H, SHI WF.Ubiquitin-specific protease 24 promotes EV71 infection by restricting K63-linked polyubiquitination of TBK1[J].Virologica Sinica,2023,38(1):75-83.

https://doi.org/10.1016/j.virs.2022.11.001

[94]

ZHANG Z, ZHANG LY, WANG B, ZHU XX, ZHAO L, CHU C, GUO Q, WEI R, YIN XQ, ZHANG YH, LI X.RNF144B inhibits LPS-induced inflammatory responsesvia binding TBK1[J].Journal of Leukocyte Biology,2019,106(6):1303-1311.

https://doi.org/10.1002/JLB.2A0819-055R

[95]

ZHANG WW, YAO L, CHEN LS, JIA P, XIANG YX, YI MS, JIA KT.Ring finger protein 34 facilitates nervous necrosis virus evasion of antiviral innate immunity by targeting TBK1 and IRF3 for ubiquitination and degradation in teleost fish[J].Journal of Virology,2023,97(6):e0053323.

https://doi.org/10.1128/jvi.00533-23

[96]

JEFFERIES CA.Regulating IRFs in IFN driven disease[J].Frontiers in Immunology,2019,10:325.

https://doi.org/10.3389/fimmu.2019.00325

[97]

CHEN XJ, XU Y, TU WH, HUANG F, ZUO YB, ZHANG HG, JIN LC, FENG Q, REN TF, HE JY, MIAO Y, YUAN YK, ZHAO Q, LIU JP, ZHANG RX, ZHU L, QIAN F, ZHU CW, ZHENG H, WANG J.Ubiquitin E3 ligase MID1 inhibits the innate immune response by ubiquitinating IRF3[J].Immunology,2021,163(3):278-292.

https://doi.org/10.1111/imm.13315

[98]

ZHANG W, WANG Q, YANG F, ZHU ZX, DUAN YY, YANG Y, CAO WJ, ZHANG KS, MA JW, LIU XT, ZHENG HX.JMJD6 negatively regulates cytosolic RNA induced antiviral signaling by recruiting RNF5 to promote activated IRF3 K48 ubiquitination[J].PLoS Pathogens,2021,17(3):e1009366.

https://doi.org/10.1371/journal.ppat.1009366

[99]

LV L, CAO MZ, BAI J, JIN L, WANG XW, GAO YN, LIU XW, JIANG P.PRV-encoded UL13 protein kinase acts as an antagonist of innate immunity by targeting IRF3-signaling pathways[J].Veterinary Microbiology,2020,250:108860.

https://doi.org/10.1016/j.vetmic.2020.108860

[100]

ZHOU ZW, CAI XL, ZHU JJ, LI Z, YU GQ, LIU X, OUYANG G, XIAO WH.Zebrafish otud6b negatively regulates antiviral responses by suppressing K63-linked ubiquitination of irf3 and irf7[J].The Journal of Immunology,2021,207(1):244-256.

https://doi.org/10.4049/jimmunol.2000891

[101]

LI Z, FAN SJ, WANG J, CHEN XY, LIAO Q, LIU X, OUYANG G, CAO H, XIAO WH.Zebrafish F-box protein fbxo3 negatively regulates antiviral response through promoting K27-linked polyubiquitination of the transcription factors irf3 and irf7[J].Journal of Immunology (Baltimore, Md: 1950),2020,205(7):1897-1908.

https://doi.org/10.4049/jimmunol.2000305

[102]

WU YX, JIN SH, LIU QX, ZHANG Y, MA L, ZHAO ZY, YANG S, LI YP, CUI J.Selective autophagy controls the stability of transcription factor IRF3 to balance type Ⅰ interferon production and immune suppression[J].Autophagy,2021,17(6):1379-1392.

https://doi.org/10.1080/15548627.2020.1761653

[103]

CHATTOPADHYAY S, KUZMANOVIC T, ZHANG Y, WETZEL JL, SEN GC.Ubiquitination of the transcription factor IRF-3 activates RIPA, the apoptotic pathway that protects mice from viral pathogenesis[J].Immunity,2016,44(5):1151-1161.

https://doi.org/10.1016/j.immuni.2016.04.009

[104]

RAJA R, SEN GC.The antiviral action of the RIG-I induced pathway of apoptosis (RIPA) is enhanced by its ability to degrade Otulin, which deubiquitinates IRF3[J].Cell Death & Differentiation,2022,29(3):504-513.

[105]

LU LF, ZHOU XY, ZHANG C, LI ZC, CHEN DD, LIU SB, LI S.Zebrafish RPZ5 degrades phosphorylated IRF7 to repress interferon production[J].Journal of Virology,2019,93(21):e01272-e01219.

[106]

LU LF, LI S, WANG ZX, LIU SB, CHEN DD, ZHANG YA.Zebrafish NDRG1a negatively regulates IFN induction by promoting the degradation of IRF7[J].The Journal of Immunology,2019,202(1):119-130.

https://doi.org/10.4049/jimmunol.1800490

[107]

ZHANG C, LU LF, LI ZC, ZHOU XY, ZHOU Y, CHEN DD, LI S, ZHANG YA.Grass carp reovirus VP56 represses interferon production by degrading phosphorylated IRF7[J].Fish & Shellfish Immunology,2020,99:99-106.

[108]

LIU BQ, LIU RB, LI WP, MAO XT, LI YN, HUANG T, WANG HL, CHEN HT, ZHONG JY, YANG B, CHAI RJ, CAO Q, JIN J, LI YY.XAF1 prevents hyperproduction of type Ⅰ interferon upon viral infection by targeting IRF7[J].EMBO Reports,2023,24(1):e55387.

https://doi.org/10.15252/embr.202255387

[109]

XING XL, XU F, WANG Y, LIU HW.Role of the OTUB1/IRF7/NOX4 axis in oxidative stress injury and inflammatory responses in mice with Parkinson's disease[J].Psychogeriatrics,2023,23(1):32-44.

https://doi.org/10.1111/psyg.12900

[110]

QI F, ZHANG X, WANG LK, REN CX, ZHAO XY, LUO JY, LU D.E3 ubiquitin ligase NEURL3 promotes innate antiviral response through catalyzing K63-linked ubiquitination of IRF7[J].FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology,2022,36(8):e22409.

[111]

LING T, WENG GX, LI J, LI CS, WANG WY, CAO LZ, RAO H, JU C, XU LG.TARBP2 inhibits IRF7 activation by suppressing TRAF6-mediated K63-linked ubiquitination of IRF7[J].Molecular Immunology,2019,109:116-125.

https://doi.org/10.1016/j.molimm.2019.02.019

[112]

LI FB, LIANG HC, YOU H, XIAO J, XIA HJ, CHEN X, HUANG MB, CHENG Z, YANG CY, LIU WJ, ZHANG HL, ZENG L, WU YY, GE F, LI Z, ZHOU WH, WEN Y, ZHOU ZM, LIU R, JIANG DW, et al.Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis[J].Signal Transduction and Targeted Therapy,2022,7:264.

https://doi.org/10.1038/s41392-022-01057-0

[113]

JI JX, DING KK, LUO T, ZHANG X, CHEN AJ, ZHANG D, LI G, THORSEN F, HUANG B, LI XG, WANG J.TRIM22 activates NF-κB signaling in glioblastoma by accelerating the degradation of IκBα[J].Cell Death & Differentiation,2021,28(1):367-381.

[114]

HAN YM, XIE JY, XU SJ, BI YJ, LI XR, ZHANG HX, IDRIS A, BAI JL, FENG RF.Encephalomyocarditis virus abrogates the interferon beta signaling pathwayvia its structural protein VP2[J].Journal of Virology,2021,95(6):e01590-e01520.

2024年第64卷第1期

PDF下载

154

引用本文

BibTeX

文章信息

doi: 10.13343/j.cnki.wsxb.20230400

接收时间：2023-06-07
首发时间：2026-03-18
出版时间：2024-01-04

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2023-06-07
录用日期：2023-10-07

基金

Fundamental Research Funds for the Central Universities of Northwest Minzu University(31920230163)

西北民族大学中央高校基本科研业务费资金(31920230163)

Fundamental Research Funds for the Central Universities of Northwest Minzu University(31920230162)

西北民族大学中央高校基本科研业务费资金(31920230162)

National Natural Science Foundation of China(32260037)

国家自然科学基金(32260037)

Ministry of Science and Technology "High-end Foreign Experts Introduction Program"(G2022187005L)

科学技术部“高端外国专家引进计划”(G2022187005L)

作者信息

1 西北民族大学生物医学研究中心生物工程与技术国家民委重点实验室, 甘肃兰州 730030

2 西北民族大学生命科学与工程学院, 甘肃兰州 730030

通讯作者:

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/wswxb/CN/10.13343/j.cnki.wsxb.20230400

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Domains	Functions	References
N: Not determine.
CARD	Produce ubiquitination and autoactivation	[6-7]
Helicase	Transduct the dsRNA-mediated signaling
CTD	Recognize viral RNA with 5′ triphosphate (ppp)
TM	Anchor to the mitochondrial outer membrane	[8]
Proline-rich region	Bind to the tumor necrosis factor receptor-related factor (TRAF) family members
RING	Equip with E3 ligase activity	[9-10]
ZFD	Regulate gene expression, cell differentiation, and embryonic development at the transcriptional and translational levels
TRAF	Interact with cell surface receptors initiates TRAF protein recruitment
KD	Regulate kinase activity
ULD	Control kinase activation, substrate presentation, and downstream signaling pathways
SDD	Mediate IKKβ and TBK1 dimerization and interaction with IκBα
NBD	Bind to NEMO
HLX	NEMO in complex with IKKβ NBD
CC	N
LZD	Bind to macromolecules
ZFD	Bind effectively to IκBα and may direct IκBα to the ULD/SDD of IKKβ
HLH	Bind to DNA and can form a dimer
DBD	Bind to DNA	[11-12]
IAD	Mediate the interaction of IRFs to other factors
Linker region	N
SRD	Receive signals from other molecules	[13-14]
ARD	Mediate the interaction between two proteins
PEST	N
RHR	Mediate form homologous and heterodimers, which in turn can bind promoter and enhancer regions of genes to regulate gene expression	[13]
NTD	Mediate synergistic binding of proteins to multiple common DNA sites
NLS	Interact with the enucleate carrier so that the protein can be transported into the nucleus
TAD	Activate target gene

Domains

Functions

References

N: Not determine.

CARD

Produce ubiquitination and autoactivation

[6-7]

Helicase

Transduct the dsRNA-mediated signaling

CTD

Recognize viral RNA with 5′ triphosphate (ppp)

Anchor to the mitochondrial outer membrane

[8]

Proline-rich region

Bind to the tumor necrosis factor receptor-related factor (TRAF) family members

RING

Equip with E3 ligase activity

[9-10]

ZFD

Regulate gene expression, cell differentiation, and embryonic development at the transcriptional and translational levels

TRAF

Interact with cell surface receptors initiates TRAF protein recruitment

Regulate kinase activity

ULD

Control kinase activation, substrate presentation, and downstream signaling pathways

SDD

Mediate IKKβ and TBK1 dimerization and interaction with IκBα

NBD

Bind to NEMO

HLX

NEMO in complex with IKKβ NBD

LZD

Bind to macromolecules

ZFD

Bind effectively to IκBα and may direct IκBα to the ULD/SDD of IKKβ

HLH

Bind to DNA and can form a dimer

DBD

Bind to DNA

[11-12]

IAD

Mediate the interaction of IRFs to other factors

Linker region

SRD

Receive signals from other molecules

[13-14]

ARD

Mediate the interaction between two proteins

PEST

RHR

Mediate form homologous and heterodimers, which in turn can bind promoter and enhancer regions of genes to regulate gene expression

[13]

NTD

Mediate synergistic binding of proteins to multiple common DNA sites

NLS

Interact with the enucleate carrier so that the protein can be transported into the nucleus

TAD

Activate target gene

Ubiquiti-nation species	Ubiquiti-nation sites	Physiological functions	Antiviral reaction
N: Not determine.
M1	Methionine (Met)	Inflammation, anti-apoptosis, NF-κB signaling activation^[20]	Epstein-Barr LMP1	TRAF1	Promote M1-linked polyubiquitination and activate downstream typical NF-κB pathway^[21]
K6	Lysine (Lys)	DNA damage repair, mitochondrial autophagy^[22-23]	PDCoV N	poIRF7	Promote K6-linked ubiquitination and inhibit porcine type Ⅰ IFN production^[24]
K11	Lysine (Lys)	Regulates the cell cycle, binds to K48 and promotes proteasomal degradation^[25]	Zika virus NS1	Caspase-1	Reduce K11-linked poly-ubiquitination and inhibit type Ⅰ interferon signaling^[26]
K27	Lysine (Lys)	DNA damage repair, antibacterial and antiviral response^[27-28]	PRV UL21	cGAS	Promote K27-linked ubiquitination and inhibit type Ⅰ interferon signaling^[29]
K29	Lysine (Lys)	Regulating the degradation of kinases^[30]	PRV UL13	STING	Promote K29-linked ubiquitination and inhibit type Ⅰ interferon signaling^[31]
K33	Lysine (Lys)	E3 ligase Nrdp1 mediates polyubiquitination of the K33 linkage of the signaling kinase Zap70, thereby terminating early TCR signaling in CD8(+) T cells^[32]	IBDV VP3	TRAF3	Reduce K33-linked ubiquitination and inhibit IFN-β expression by blocking TRAF3-TBK1 complex formation^[33]
K48	Lysine (Lys)	Mediates protein degradation by 26S proteasome^[34]	GCRV VP4	RIG-1	Promote K48-linked ubiquitination and inhibit type Ⅰ interferon signaling^[35]
K63	Lysine (Lys)	Activate the antiviral signaling pathway^[36-38]	IBV PLpro	MDA5	Reduce K63-linked ubiquitination and inhibit type Ⅰ interferon signaling^[39]
G76	Glycine (Gly)	Connecting each ubiquitin site, formation of a ubiquitin chain by constructing an isopeptide bond between G76 of one ubiquitin and a specific lysine residue of the next ubiquitin^[40]	N	N	N

Ubiquiti-nation species

Ubiquiti-nation sites

Physiological functions

Antiviral reaction

Virus proteins

Substrates

Effects

N: Not determine.

Methionine (Met)

Inflammation, anti-apoptosis, NF-κB signaling activation^[20]

Epstein-Barr LMP1

TRAF1

Promote M1-linked polyubiquitination and activate downstream typical NF-κB pathway^[21]

Lysine (Lys)

DNA damage repair, mitochondrial autophagy^[22-23]

PDCoV N

poIRF7

Promote K6-linked ubiquitination and inhibit porcine type Ⅰ IFN production^[24]

K11

Lysine (Lys)

Regulates the cell cycle, binds to K48 and promotes proteasomal degradation^[25]

Zika virus NS1

Caspase-1

Reduce K11-linked poly-ubiquitination and inhibit type Ⅰ interferon signaling^[26]

K27

Lysine (Lys)

DNA damage repair, antibacterial and antiviral response^[27-28]

PRV UL21

cGAS

Promote K27-linked ubiquitination and inhibit type Ⅰ interferon signaling^[29]

K29

Lysine (Lys)

Regulating the degradation of kinases^[30]

PRV UL13

STING

Promote K29-linked ubiquitination and inhibit type Ⅰ interferon signaling^[31]

K33

Lysine (Lys)

E3 ligase Nrdp1 mediates polyubiquitination of the K33 linkage of the signaling kinase Zap70, thereby terminating early TCR signaling in CD8(+) T cells^[32]

IBDV VP3

TRAF3

Reduce K33-linked ubiquitination and inhibit IFN-β expression by blocking TRAF3-TBK1 complex formation^[33]

K48

Lysine (Lys)

Mediates protein degradation by 26S proteasome^[34]

GCRV VP4

RIG-1

Promote K48-linked ubiquitination and inhibit type Ⅰ interferon signaling^[35]

K63

Lysine (Lys)

Activate the antiviral signaling pathway^[36-38]

IBV PLpro

MDA5

Reduce K63-linked ubiquitination and inhibit type Ⅰ interferon signaling^[39]

G76

Glycine (Gly)

Connecting each ubiquitin site, formation of a ubiquitin chain by constructing an isopeptide bond between G76 of one ubiquitin and a specific lysine residue of the next ubiquitin^[40]