微生物学报

病毒 Viruses	功能 Function
单纯疱疹病毒1 Herpes simplex virus-1 (HSV-1)	非特异性结合并降低HSV-1基因组可及性以抑制感染^[57]；通过液-液相分离机制启动先天免疫信号并抑制HSV-1转录^[58]；与DNA-PK形成抗病毒信号轴，调控先天免疫应答^[59] Indiscriminately binds to and diminishes accessibility of the HSV-1 genome to suppress infection^[57]; initiates innate immune signaling through liquid-liquid phase separation and suppresses viral transcription^[58]; IFI16 and DNA-PK form an antiviral signaling axis that governs innate immunity to HSV-1 infection^[59]
爱泼斯坦-巴尔病毒 Epstein-barr virus (EBV)	与HCM核心组分协同作用，沉默EBV关键裂解开关蛋白，从而确保病毒在B淋巴细胞中持续处于潜伏状态^[8] Partners with core components of the HCM to silence the key EBV lytic switch protein, ensuring continued viral latency in B lymphocytes^[8]
人巨细胞病毒 Human cytomegalovirus (HCMV)	与ChREBP协同作用下调GLUT4的转录激活，减少HCMV诱导的脂肪合成酶转录，导致脂质合成减少，抑制病毒颗粒的从头形成^[45] Cooperates with ChREBP to downregulate GLUT4 transcriptional activation, reduces HCMV-induced transcription of lipogenic enzymes, leading to diminished lipid synthesis, and curbs the formation of viral particles^[45]
卡波氏肉瘤相关疱疹病毒 Kaposi’s sarcoma-associated herpesvirus (KSHV)	PAN RNA协助NAT10招募IFI16 mRNA，从而提高IFI16的翻译效率并诱导炎症小体的激活^[44]；招募HDAC1和HDAC2去乙酰化KSHV的LANA，维持病毒潜伏^[46] PAN RNA assists in NAT10 recruitment to IFI16 mRNA, resulting in increased IFI16 translation efficiency and inflammasome induction^[44]; recruits HDAC1 and HDAC2 to deacetylate LANA of KSHV, facilitating its latency^[46]
痘病毒 Vaccinia virus (VACV)	IFI16-iso1优先与细胞质复制的VACV共定位，诱导干扰素刺激基因的转录，激活抗病毒免疫反应；IFI16-iso2可清除入侵VACV^[16] IFI16-iso1 preferentially colocalizes with cytoplasm-replicating VACV, induces the transcription of IFN-stimulated genes, and elicits the antiviral immune response; IFI16-iso2 can clear invaded VACV^[16]
腺相关病毒2型 Adeno-associated virus type 2 (AAV2)	通过干扰Sp1介导的病毒启动子的反式激活，以一种与免疫调节无关的方式限制AAV2转导^[47] Restricts AAV2 transduction in an immune-modulatory independent way by interfering with SP1-mediated transactivation of the viral promoters^[47]
人乳头瘤病毒 Human papillomavirus (HPV)	通过促进HPV DNA异染色质化，抑制HPV18早期和晚期启动子活性，进而限制HPV的复制和基因表达^[48] Restricts HPV replication and gene expression by promoting the assembly of heterochromatin on HPV DNA and repressing the activities of both early and late HPV18 promoters^[48]
乙型肝炎病毒 Hepatitis B virus (HBV)	通过靶向cccDNA的ISRE，整合先天免疫激活与表观遗传调控，阻断HBV cccDNA的功能^[49] Inhibits the function of HBV cccDNA by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA^[49]
基孔肯雅病毒 Chikungunya virus (CHIKV)	通过与CHIKV基因组结合，以不依赖干扰素信号或DNA结合转录活性的方式抑制CHIKV复制^[50] Restricts CHIKV replication independent of interferon-signaling or DNA-binding transcriptional activity by binding to CHIKV genomes^[50]
尼帕病毒 Nipah virus (NiV)	识别泄漏至胞质中的线粒体DNA (mitochondrial DNA, mtDNA)，并主要通过激活STING/NF-κB信号及炎症因子反应，以控制NiV感染^[31] Recognizes mtDNA that leaks into the cytoplasm and primarily activates STING/NF-κB and inflammatory cytokines response to control NiV infection^[31]

病毒 Viruses	功能 Function
单纯疱疹病毒1 Herpes simplex virus-1 (HSV-1)	非特异性结合并降低HSV-1基因组可及性以抑制感染^[57]；通过液-液相分离机制启动先天免疫信号并抑制HSV-1转录^[58]；与DNA-PK形成抗病毒信号轴，调控先天免疫应答^[59] Indiscriminately binds to and diminishes accessibility of the HSV-1 genome to suppress infection^[57]; initiates innate immune signaling through liquid-liquid phase separation and suppresses viral transcription^[58]; IFI16 and DNA-PK form an antiviral signaling axis that governs innate immunity to HSV-1 infection^[59]
爱泼斯坦-巴尔病毒 Epstein-barr virus (EBV)	与HCM核心组分协同作用，沉默EBV关键裂解开关蛋白，从而确保病毒在B淋巴细胞中持续处于潜伏状态^[8] Partners with core components of the HCM to silence the key EBV lytic switch protein, ensuring continued viral latency in B lymphocytes^[8]
人巨细胞病毒 Human cytomegalovirus (HCMV)	与ChREBP协同作用下调GLUT4的转录激活，减少HCMV诱导的脂肪合成酶转录，导致脂质合成减少，抑制病毒颗粒的从头形成^[45] Cooperates with ChREBP to downregulate GLUT4 transcriptional activation, reduces HCMV-induced transcription of lipogenic enzymes, leading to diminished lipid synthesis, and curbs the formation of viral particles^[45]
卡波氏肉瘤相关疱疹病毒 Kaposi’s sarcoma-associated herpesvirus (KSHV)	PAN RNA协助NAT10招募IFI16 mRNA，从而提高IFI16的翻译效率并诱导炎症小体的激活^[44]；招募HDAC1和HDAC2去乙酰化KSHV的LANA，维持病毒潜伏^[46] PAN RNA assists in NAT10 recruitment to IFI16 mRNA, resulting in increased IFI16 translation efficiency and inflammasome induction^[44]; recruits HDAC1 and HDAC2 to deacetylate LANA of KSHV, facilitating its latency^[46]
痘病毒 Vaccinia virus (VACV)	IFI16-iso1优先与细胞质复制的VACV共定位，诱导干扰素刺激基因的转录，激活抗病毒免疫反应；IFI16-iso2可清除入侵VACV^[16] IFI16-iso1 preferentially colocalizes with cytoplasm-replicating VACV, induces the transcription of IFN-stimulated genes, and elicits the antiviral immune response; IFI16-iso2 can clear invaded VACV^[16]
腺相关病毒2型 Adeno-associated virus type 2 (AAV2)	通过干扰Sp1介导的病毒启动子的反式激活，以一种与免疫调节无关的方式限制AAV2转导^[47] Restricts AAV2 transduction in an immune-modulatory independent way by interfering with SP1-mediated transactivation of the viral promoters^[47]
人乳头瘤病毒 Human papillomavirus (HPV)	通过促进HPV DNA异染色质化，抑制HPV18早期和晚期启动子活性，进而限制HPV的复制和基因表达^[48] Restricts HPV replication and gene expression by promoting the assembly of heterochromatin on HPV DNA and repressing the activities of both early and late HPV18 promoters^[48]
乙型肝炎病毒 Hepatitis B virus (HBV)	通过靶向cccDNA的ISRE，整合先天免疫激活与表观遗传调控，阻断HBV cccDNA的功能^[49] Inhibits the function of HBV cccDNA by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA^[49]
基孔肯雅病毒 Chikungunya virus (CHIKV)	通过与CHIKV基因组结合，以不依赖干扰素信号或DNA结合转录活性的方式抑制CHIKV复制^[50] Restricts CHIKV replication independent of interferon-signaling or DNA-binding transcriptional activity by binding to CHIKV genomes^[50]
尼帕病毒 Nipah virus (NiV)	识别泄漏至胞质中的线粒体DNA (mitochondrial DNA, mtDNA)，并主要通过激活STING/NF-κB信号及炎症因子反应，以控制NiV感染^[31] Recognizes mtDNA that leaks into the cytoplasm and primarily activates STING/NF-κB and inflammatory cytokines response to control NiV infection^[31]

干扰素-γ诱导蛋白16调控天然免疫及病毒感染的研究进展

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李向茸 ¹^,²^,³ , 董平安 ¹^,³^,⁴ , 莫荣纤 ¹^,³^,⁴ , 冯若飞 ¹^,²^,³

微生物学报 | 综述 2026,66(2): 481-494

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微生物学报 | 综述 2026, 66(2): 481-494

干扰素-γ诱导蛋白16调控天然免疫及病毒感染的研究进展

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李向茸¹^,²^,³, 董平安¹^,³^,⁴, 莫荣纤¹^,³^,⁴, 冯若飞¹^,²^,³

作者信息

^1.西北民族大学，生物医学研究中心，细胞基质疫苗关键技术与产业化教育部工程研究中心，甘肃兰州

^2.西北民族大学，生物医学研究中心，甘肃省动物细胞技术创新中心，甘肃兰州

^3.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

^4.西北民族大学生命科学与工程学院，甘肃兰州

Research progress on the regulation of innate immunity and viral infection by IFN-γ inducible protein 16

Xiangrong LI¹^,²^,³, Ping’an DONG¹^,³^,⁴, Rongqian MO¹^,³^,⁴, Ruofei FENG¹^,²^,³

Affiliations

^1.Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu, China

^2.Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu, China

^3.Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu, China

^4.School of Life Sciences and Engineering, Northwest Minzu University, Lanzhou, Gansu, China

出版时间: 2026-02-04 doi: 10.13343/j.cnki.wsxb.20250365

文章导航

摘要

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干扰素-γ诱导蛋白16 (interferon gamma-inducible protein 16, IFI16)是含pyrin和造血表达、干扰素诱导特性和核定位(hematopoietic expression, interferon-inducible nature, and nuclear localization, HIN)结构域的蛋白质(pyrin and HIN domain-containing protein, PYHIN)家族的重要成员，其独特的分子结构使其能够识别细胞内的多种核酸分子。作为一种关键的免疫调节因子，IFI16可通过多种途径参与天然免疫信号转导，在宿主抗病毒防御中发挥重要作用。本文综述了IFI16的分子特征及其在天然免疫和病毒感染中的调控机制，为抗病毒感染的治疗靶点及药物开发提供理论依据。

关键词

干扰素-γ诱导蛋白16 / DNA传感器 / 天然免疫 / 病毒感染

Abstract

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Interferon gamma-inducible protein 16 (IFI16), a pivotal member of the pyrin and hematopoietic expression, interferon-inducible nature, and nuclear localization (HIN) domain-containing protein (PYHIN) family, possesses a unique molecular structure that enables it to recognize diverse nucleic acid molecules within cells. As a key immunoregulatory factor, IFI16 participates in the transduction of innate immune signaling through multiple pathways and plays a significant role in host antiviral defense. This review systematically summarized the molecular characteristics of IFI16 and its regulatory mechanisms in innate immunity and viral infection, aiming to provide a theoretical basis for the development of therapeutic targets and antiviral drugs.

Key words

interferon gamma-inducible protein 16 / DNA sensor / innate immunity / viral infection

引用本文

李向茸, 董平安, 莫荣纤, 冯若飞. 干扰素-γ诱导蛋白16调控天然免疫及病毒感染的研究进展. 微生物学报, 2026 , 66 (2) : 481 -494 . DOI: 10.13343/j.cnki.wsxb.20250365

Xiangrong LI, Ping’an DONG, Rongqian MO, Ruofei FENG. Research progress on the regulation of innate immunity and viral infection by IFN-γ inducible protein 16[J]. Acta Microbiologica Sinica, 2026 , 66 (2) : 481 -494 . DOI: 10.13343/j.cnki.wsxb.20250365

正文

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先天免疫系统首先利用模式识别受体(pattern recognition receptors, PRRs)识别保守的病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)和损伤相关分子模式(damage-associated molecular patterns, DAMPs)，如肽聚糖、脂多糖(lipopolysaccharide, LPS)和核酸等^[1]，进而启动免疫级联反应，抵御病原体的入侵。现有研究已鉴定出多种PRRs，包括视黄酸诱导基因I (retinoic acid inducible gene I, RIG-I)样受体 (retinoic acid-inducible gene-I-like receptors, RLR)、Toll样受体(Toll-like receptors, TLR)、环鸟苷酸-单磷酸腺苷合成酶家族(cyclic guanosine monophosphate-adenosine monophosphate synthase, cGAS)以及含pyrin和造血表达、干扰素诱导特性和核定位(hematopoietic expression, interferon-inducible nature, and nuclear localization, HIN)结构域的蛋白质(pyrin and HIN domain-containing protein, PYHIN)家族(也称为HIN-200蛋白家族或干扰素诱导p200蛋白家族)等^[2]。PYHIN家族是由病原体感染和应激条件(如DNA断裂)激活的DNA传感器之一，因其在启动先天免疫应答中的重要作用，近年来备受研究人员关注。在人类中，PYHIN家族成员包括黑色素瘤缺乏因子2 (absent in melanoma 2, AIM2)、干扰素-γ诱导蛋白16 (interferon gamma-inducible protein 16, IFI16)、骨髓细胞核分化抗原(myeloid cell nuclear differentiation antigen, MNDA)和干扰素诱导蛋白X (interferon-inducible protein X, IFIX)^[3]。

近年来，科研人员围绕PYHIN家族成员在宿主免疫调控中的作用机制展开了系统性研究，尤其在天然免疫信号转导与抗病毒感染领域取得了显著进展。IFI16作为PYHIN家族的核心成员，是一种独特的DNA传感器，它不仅能感知细胞质中的DNA，还能感知细胞核中的DNA，进而触发不同的先天免疫反应^[4]。Erttmann等^[5]研究发现，IFI16能够激活干扰素刺激基因(stimulator of interferon gene, STING)依赖性I型干扰素(type I interferon, IFN-I)的产生，促进凋亡相关颗粒样蛋白(apoptosis-associated speck-like protein containing a CARD, ASC)介导的炎症小体形成以及白细胞介素-1β (interleukin-1β, IL-1β)的成熟。此外，IFI16还能感知多种病毒的双链DNA (double-stranded DNA, dsDNA)，如乙型肝炎病毒(hepatitis B virus, HBV)^[6]、单纯疱疹病毒1型(herpes simplex virus-1, HSV-1)^[7]、爱泼斯坦-巴尔病毒(epstein-barr virus, EBV)等^[8]。Fu等^[7]研究证实，IFI16检测到病毒DNA或RNA后，会通过激活STING依赖性的信号转导，进而诱导IFN-I、促炎细胞因子及趋化因子的产生以发挥抗病毒作用。然而，部分病毒已进化出独特机制来拮抗IFI16的功能，如通过诱导IFI16的降解或使其错误定位、进行表观遗传修饰，或是干扰其与其他宿主因子结合等方式，从而为自身的复制与传播创造有利条件。本文综述了IFI16的分子特征及其在天然免疫及病毒感染中的调控作用，旨在为抗病毒感染治疗靶点的开发及药物设计提供理论依据。

1 IFI16的分子特征

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1992年，Choubey等^[9]首次在淋巴样细胞中鉴定出IFI16蛋白，后续研究进一步证实IFI16与髓系细胞的活化和分化密切相关，如今它已被明确划归为PYHIN蛋白家族，其独特的分子结构和功能特征使其在多种生理和病理过程中发挥着重要作用。

1.1 IFI16的基本结构

在结构上，IFI16的N末端存在pyrin结构域(pyrin domain, PYD)，该结构域参与同型蛋白-蛋白相互作用，是细胞凋亡、炎症和先天性免疫信号通路所必需的结构元件；而与其他PYHIN蛋白家族成员不同的是，IFI16的C末端有2个HIN结构域^[10]，分别称为HIN-A和HIN-B，这些结构域可能与蛋白质或非自身DNA结合有关^[11]；此外，在2个HIN中间还存在一个丝氨酸/酪氨酸/脯氨酸(serine/tyrosine/proline, S/T/P)重复结构，该结构的长度受限制性mRNA剪接酶的调控，从而产生了3种亚型的IFI16 (A–C)^[12]。其具体结构如图1所示。

1.2 IFI16的亚细胞定位

IFI16因分子结构中包含核定位信号(nuclear localization signal, NLS)，最初被报道为一种核蛋白^[13]。与其他PYHIN家族成员专属细胞核或细胞质的定位模式不同，IFI16蛋白已在多种类型细胞的细胞核(核仁和核质)、细胞质和这2个区室中被检测到^[14]。此外，研究还发现IFI16可以在细胞质和细胞核之间穿梭^[15-17]。尽管如此，目前关于调控IFI16蛋白在细胞核与细胞质之间再分配的分子机制尚未完全阐明，可能涉及IFI16基因多态性、蛋白-蛋白相互作用、激素调控以及翻译后修饰等多重因素的协同作用。

1.3 IFI16识别的核酸分子

PYHIN家族的大部分成员通过其HIN结构域以非序列特异性的方式与dsDNA结合，且这种结合能力较强^[18]。然而，IFI16的HIN-B表现出较弱的dsDNA结合能力。尽管IFI16结合的核酸分子主要为dsDNA，但研究发现在特定情况下，IFI16也能与超螺旋或十字形DNA等其他形式的核苷酸结构相结合^[19]。此外，IFI16还可以与单链DNA (single-stranded DNA, ssDNA)的碱基配对，这种现象与发生在逆转录中的病毒cDNA识别机制类似^[20]。例如，IFI16能够与人类免疫缺陷病毒1型(human immunodeficiency virus-1, HIV-1)的逆转录中间体结合^[21]。目前关于IFI16是否能够识别RNA-DNA杂交体尚不明确。Jiang等^[22]研究发现，小干扰RNA (small interfering RNA, siRNA)能同时结合IFI16和RIG-I，进而形成IFI16-RIG-I-siRNA三元复合物，最终诱导III型IFN的表达。然而，在dsDNA存在的情况下，IFI16会从IFI16-RIG-I-siRNA复合物中解离，转而与dsDNA结合形成IFI16-dsDNA复合物。尽管IFI16与siRNA的结合能力显著弱于其与dsDNA的结合能力，但这些研究结果证实，IFI16作为一种关键的DNA传感器，不仅能够识别多种形式的DNA，还具备识别RNA分子的能力。

1.4 IFI16的表达调控

IFI16的表达调控受多种因素影响，包括转录水平、翻译后修饰、细胞周期、病毒感染以及DNA损伤等。在转录调控方面，干扰素(如IFN-α、IFN-β)、IL-6及肿瘤坏死因子分别通过转录因子-1、信号转导与转录激活子3和核因子κB (nuclear factor kappa B, NF-κB)依赖的方式诱导IFI16的mRNA表达^[23]；同时，其mRNA稳定性受转录后m⁶A修饰调控，该修饰由甲基转移酶复合物结构稳定剂——Wilms肿瘤因子1相关蛋白(Wilms’ tumor 1-associating protein, WTAP)介导^[24]。在翻译后修饰方面，IFI16多个位点可发生乙酰化、磷酸化、泛素化和类泛素化(sumoylation, SUMO)修饰^[25-26]。其中，IFI16的乙酰化由乙酰转移酶催化，通过将乙酰辅酶A的乙酰基转移到赖氨酸(Lys, K)残基上实现，目前已经鉴定的乙酰化位点包括K45、K99和K128等，IFI16的乙酰化对其胞质转移和下游信号转导至关重要^[25-26]。Wang等^[26]研究证实，沉默信息调节因子1与IFI16结合，通过降低IFI16的乙酰化水平抑制IFI16向细胞质转移来负向调控细胞抗病毒反应，从而削弱针对DNA病毒的先天免疫防御。IFI16的磷酸化具有位点特异性和信号依赖性，主要由丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)或DNA损伤反应激酶家族催化，多位于丝氨酸/苏氨酸残基上，不同位点的修饰对应着不同的功能效应^[25]。IFI16的泛素化修饰是IFI16蛋白稳定性及功能调控的重要开关，由泛素分子与IFI16特定赖氨酸残基共价连接实现。Gao等^[27]研究发现，E3泛素连接酶TRIM21可介导IFI16的泛素化降解，而泛素特异性蛋白酶12通过其去泛素化酶活性抑制IFI16的蛋白酶体依赖性降解，从而维持其稳定性^[7]。SUMO化修饰是IFI16功能调控的另一关键翻译后修饰方式，通过SUMO分子与IFI16特定赖氨酸残基共价结合实现，目前已经鉴定的SUMO化位点包括K116、K128、K561和K683^[25]，可能通过调控IFI16的核内稳定性及与染色质/病毒DNA的结合，或是抑制其泛素-蛋白酶体降解而发挥作用。此外，IFI16的表达与细胞类型及细胞周期相关。病毒感染以及细胞内的DNA损伤反应均能激活IFI16的表达，进而增强宿主细胞的抗病毒免疫反应，或参与DNA损伤修复与细胞周期调控过程^[28-29]。这些因素相互协作使IFI16的表达得到精准调控，既能充分发挥其生物学功能，又能有效规避因过度激活而可能引发的潜在风险。

2 IFI16在天然免疫中的调控作用

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IFI16作为天然免疫中的关键DNA感应器，在宿主防御病原体入侵和维持细胞稳态中发挥着重要作用。IFI16能与几种经典的干扰素信号通路和炎症因子信号通路上的某些关键蛋白分子结合，影响整个信号转导过程，从而对天然免疫信号通路发挥重要的调控作用(图2)。

2.1 IFI16对cGAS-STING信号通路的调控作用

研究已证实，DNA诱导IFN的产生主要依赖于cGAS-STING-TANK结合激酶1 (TANK-binding kinase 1, TBK1)-干扰素调节因子3 (interferon regulatory factor 3, IRF3)轴。cGAS作为一种先天性DNA传感器，能够识别并结合非自身的DNA，并催化生成第二信使-2′,3′-环鸟苷单磷酸-腺苷单磷酸(2′,3′-cyclic GMP-AMP, 2′,3′-cGAMP)。2′,3′- cGAMP与STING结合后诱导其构象改变，从而激活后者，使STING能够招募TBK1，进而催化IRF3的磷酸化和核易位，最终诱导IFN-I的转录^[30]。作为细胞内DNA识别受体之一，IFI16在该通路上也发挥重要作用，已发现IFI16能增强cGAS介导的IFN的表达^[31]；胞质中的IFI16对于DNA诱导的IRF3和NF-κB的核易位以及IFN-β的表达必不可少。此外，IFI16还能够直接与STING相互作用，促使STING招募TBK1^[32]。然而，STING又通过招募E3连接酶TRIM21，经泛素-蛋白酶体途径促进IFI16的降解^[33]，从而避免抗病毒免疫过程中IFN-I的过量产生，防止自身免疫性疾病的发生。

2.2 IFI16对RLRs信号通路的调控作用

RLRs信号通路是固有免疫中清除RNA病毒的关键通路，RIG-I、黑色素瘤分化相关基因5 (melanoma differentiation-associated gene 5, MDA5)、遗传学和生理学实验室蛋白2 (laboratory of genetics and physiology 2, LPG2)、线粒体抗病毒信号蛋白(mitochondrial antiviral signaling protein, MAVS)被认为是该通路上的关键分子。Jiang等^[22]研究揭示，IFI16不仅能直接与RNA聚合酶II结合并将其招募至RIG-I启动子上，以此上调RIG-I的转录，还能通过其PYD结构域与RIG-I蛋白结合，从而促进RIG-I的激活，是甲型流感病毒(influenza A virus, IAV)感染过程中RIG-I信号的正向调节因子。在猪繁殖与呼吸障碍综合征病毒(porcine reproductive and respiratory syndrome virus, PRRSV)感染MARC-145细胞时IFI16可以与MAVS相互作用，并以MAVS依赖性的方式促进IFN-I的产生^[34]。此外，IFI16还能以不依赖于STING的方式调控RIG-I、MAVS的表达，从而影响IFN-I的产生^[35]。这些研究表明，IFI16通过多种机制增强RIG-I/MAVS介导的IFN-I产生，为抗病毒治疗提供了潜在的靶点。

2.3 IFI16对TLR信号通路的调控作用

Bawadekar等^[36]研究表明，IFI16能够激活p38 MAPK、p44/42 MAPK以及NF-κB，从而导致趋化因子(IL-6、IL-8、CCL2、CCL5和CCL20)、细胞间黏附分子(ICAM-1和VCAM-1)以及TLR4的表达增多，这揭示了IFI16作为一种DAMPs，可通过髓性分化因子88依赖性TLR途径传递炎症信号。此外，IFI16已被证实是TLR4的一种特异性配体，当IFI16与LPS组成复合物时能够迅速刺激TLR4介导的炎症反应^[37]。这些发现揭示了IFI16在炎症信号传导中的重要作用，以及其在调节免疫反应中的潜在机制。

2.4 IFI16对炎症小体的调控作用

炎症小体作为天然免疫系统的关键组成部分，能够识别PAMPs和DAMPs，招募并激活半胱天冬酶-1 (caspase-1)，促使促炎细胞因子的释放或诱导细胞焦亡，并在宿主防御病原体感染中发挥关键调节作用^[38]。当IFI16蛋白在细胞核内识别到病毒基因组后可以与衔接分子ASC和效应蛋白pro-caspase-1在细胞核内组装成多蛋白炎症复合体^[39-40]。携带炎症复合体的IFI16也会从细胞核转移至细胞质，激活caspase-1，最终促进IL-1β和IL-18的成熟与分泌^[39]，这一过程对于宿主的抗病毒免疫反应至关重要。Monroe等^[41]研究发现，IFI16在CD4⁺ T细胞中是HIV感染介导的细胞焦亡所必需的，通过激活caspase-1来促进炎症因子的成熟和分泌。Ansari等^[15]研究发现，IFI16能识别细胞核内的疱疹病毒基因组，从而形成IFI16-ASC-Caspase-1炎性小体复合物并产生IL-1β，而且IFI16在细胞核内识别HSV-1基因组还会导致细胞质中STING的激活以及IFN-β的产生。Jiang等^[42]研究发现，IFI16的乙酰化修饰是其炎性小体激活和IFN-β产生的先天反应所必需的。此外，Wang等^[43]发现，IFI16的转录异构体IFI16-β不仅可通过与AIM2相互作用阻碍AIM2-ASC复合体的形成，还能将细胞质中dsDNA隔离，使其无法被AIM2感应，从而对AIM2炎性小体的激活发挥抑制作用。总之，IFI16与炎症小体的关系密切相关，它们可以相互作用从而调节炎症和免疫应答。

3 IFI16在病毒感染中的调控作用

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IFI16作为一种多功能的DNA感受器，在宿主防御DNA病毒和RNA病毒感染中发挥着关键作用。然而，病毒在长期进化过程中也发展出多种策略以拮抗IFI16介导的宿主抗病毒免疫反应。

3.1 IFI16对DNA病毒的调控作用

研究表明，IFI16是HSV-1、EBV、卡波氏肉瘤相关疱疹病毒(Kaposi’s sarcoma-associated herpesvirus, KSHV)等疱疹病毒的重要限制因子，主要通过激活炎性小体、触发干扰素反应以及通过表观遗传修饰沉默疱疹病毒的裂解基因进而阻止病毒的复制和传播^[8,44]。Xu等^[8]研究发现，IFI16可通过与组成型异染色质(heterochromatin machinery, HCM)结合来限制EBV裂解激活，并证实IFI16与HCM的核心成分之间存在相互作用。在人巨细胞病毒(human cytomegalovirus, HCMV)感染原代人包皮成纤维细胞时，IFI16还可通过与碳水化合物反应元件结合蛋白(carbohydrate-response element-binding protein, ChREBP)互作下调葡萄糖转运蛋白4 (glucose transporter 4, GLUT4)的转录激活，减少HCMV诱导的造脂酶的转录，导致脂质合成减少，从而限制囊膜化病毒粒子的从头合成，揭示了其在HCMV复制中调控葡萄糖和脂质代谢的新作用及抗病毒治疗潜力^[45]。Li等^[16]研究发现，IFI16的同源异构体2 (isoform 2 of IFI16, IFI16-iso2)具有核-质穿梭能力，能够显著清除入侵的HSV-1和痘病毒(vaccinia virus, VACV)，并且还证明具有细胞质和核定位的IFI16亚型在对抗DNA病毒介导的先天免疫中发挥着不同的作用。Ghosh等^[46]研究发现，IFI16能够招募组蛋白脱乙酰酶1 (histone deacetylase 1, HDAC1)和HDAC2，对KSHV的潜伏相关核抗原(latency-associated nuclear antigen, LANA)进行去乙酰化修饰，从而促进KSHV的潜伏感染，这一发现揭示了IFI16在KSHV潜伏调控中的新机制。Sutter等^[47]研究表明，IFI16通过干扰野生型腺相关病毒2型(adeno-associated virus type 2, AAV2)和AAV2载体启动子的Sp1依赖性的转录激活作用，从而以一种独立于免疫调节的方式限制AAV2的转导。Cigno等^[48]研究证明，IFI16可通过促进异染色质DNA的组装抑制HPV18早期和晚期启动子的活性，从而降低人乳头瘤病毒(human papillomavirus, HPV) 18型在NIKS和U2OS细胞中的转录及复制，揭示了IFI16参与HPV基因表达和复制的表观遗传调控。此外，Yang等^[49]研究证实，IFI16可通过靶向识别和结合HBV共价闭合环状DNA (covalently closed circular DNA, cccDNA)中的干扰素刺激反应元件抑制cccDNA的转录，从而限制HBV的体外复制，提示其可能作为抗HBV感染的新型治疗靶标。综上所述，IFI16作为多功能抗病毒因子在DNA病毒生命周期的多个关键环节中发挥精准调控作用(表1)。

3.2 IFI16对RNA病毒的调控作用

尽管DNA病毒和RNA病毒被不同类别的PRRs识别，但DNA病毒和RNA病毒感知机制之间可能存在部分重叠^[18]。Kim等^[50]研究发现，IFI16可直接结合基孔肯雅病毒(chikungunya virus, CHIKV)基因组RNA，以不依赖干扰素信号或DNA结合转录活性的方式限制病毒复制和成熟，提示IFI16可能在RNA病毒感染中发挥调控作用。Wichit等^[51]研究进一步表明，CHIKV感染HFF1和人胚胎肾细胞后IFI16表达上调，IFI16的外源表达抑制了CHIKV的体外感染，而内源性沉默IFI16显著增加了病毒复制。副黏病毒科的尼帕病毒(Nipah virus, NiV)与麻疹病毒(measles virus, MeV)感染诱导的合胞体可引发线粒体损伤，导致线粒体DNA泄漏至胞质，并被细胞内的cGAS和IFI16等DNA传感器检测到；其中IFI16主要激活STING/NF-κB和炎症细胞因子反应，从而对NiV和MeV感染发挥抗病毒作用^[31]。Chang等^[34]研究发现，IFI16可以促进PRRSV诱导的IFN-β的产生，与MAVS在细胞内直接互作，并以MAVS依赖的方式发挥抗PRRSV的作用。此外，IFI16还可以在细胞核内感知PRRSV的线性RNA，激活caspase-1和IL-1β的成熟以抑制PRRSV感染^[52]。Jiang等^[22]研究发现，IAV感染在体外和体内均可以显著诱导IFI16蛋白在细胞核与细胞质中的表达；而IFI16不仅能直接结合IAV基因组RNA，还可通过正向调控RIG-I介导的信号通路激活增强IFN-I产生及下游抗病毒免疫反应，进而抑制IAV的体外复制。Mishra等^[53]研究揭示，IFI16还可通过结合IAV基因组RNA分别经由STING-TBK1及pro-caspase-1信号轴诱导IFN-I、IFN-III和促炎细胞因子的产生，从而促进感染细胞发生凋亡与焦亡，表明该蛋白在IAV感染细胞中对程序性死亡通路的激活至关重要。IFI16在禽呼肠孤病毒(avian reovirus, ARV)诱导的细胞免疫抑制过程中也发挥着关键作用，它通过其HIN-A与HIN-B结构域结合ARV p17蛋白的第61–119位氨基酸抑制ARV的体外复制^[54]。同样地，本课题组前期研究发现，IFI16能够与脑心肌炎病毒(encephalomycarditis virus, EMCV)的衣壳蛋白VP2相互作用，并通过增强EMCV诱导的IFN-I信号通路在体外抑制EMCV的增殖^[55]。此外，Hotter等^[56]研究还发现，IFI16可以通过结合并干扰驱动病毒基因表达的宿主转录因子Sp1的表达，以不依赖免疫感知的方式抑制HIV-1的转录和潜伏病毒的活化。如表1所示，宿主DNA传感器IFI16不仅在DNA病毒感染中发挥抗病毒作用，而且对多种RNA病毒复制也具有负调控作用。

3.3 病毒对IFI16的拮抗机制

近年来研究表明，许多病毒已演化出各自独特的对抗宿主抗病毒因子IFI16的策略，例如通过诱导其蛋白降解、干扰亚细胞定位、进行表观遗传修饰或阻断与其他宿主因子的结合等机制，从而逃避宿主免疫监视体系，促进自身复制和传播。例如，HSV-1的即刻早期蛋白ICP0以蛋白酶体依赖的方式诱导IFI16降解，有利于HSV-1复制^[60]；HCMV的病毒蛋白UL97和pUL83可使IFI16从细胞核错误定位到细胞质中^[61]；而HCMV和HSV-1感染还能诱导IFI16的第90位赖氨酸发生乳酸化修饰，抑制抗病毒细胞因子(如IFN-β、CXCL10)的表达，进而促进病毒逃逸宿主免疫系统的监测^[62]；HPV E7蛋白通过招募E3泛素连接酶TRIM21来泛素化并降解IFI16炎性小体，从而抑制细胞焦亡，逃避免疫系统的识别^[33]；HIV-1 C亚型的长末端重复序列启动子中存在一个额外的NF-κB结合位点，使其能够逃避核PYHIN蛋白的限制作用^[63]。此外，本课题组研究发现EMCV的VP2蛋白通过其N端结构域与IFI16结合，并借助C端结构域激活caspase-3依赖性凋亡途径，诱导IFI16蛋白降解；同时，VP2蛋白将IFI16阻滞于细胞核内，削弱其胞浆分布，双重抑制IFI16-STING介导的IFN-β活化，减弱由IFI16介导的抗病毒反应，从而促进病毒自身增殖^[55]。这一发现揭示了EMCV逃逸宿主先天免疫的一种新机制，为靶向VP2-IFI16互作设计抗病毒药物提供了重要理论依据。Prelli Bozzo等^[64]利用CRISPR/Cas9筛选技术探究HIV-1中的抗病毒关键因子，发现IFI16是HIV-1辅助蛋白Nef的靶点，IFI16的抗病毒作用能够被Nef抵消。这些策略均体现了病毒对IFI16功能的精准破坏，为病毒的感染和传播创造了有利条件。

4 总结与展望

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IFI16作为一种关键的细胞传感器，除参与细胞增殖、分化、衰老等多种细胞进程外，还能够增强cGAS-STING、RIG-I-MAVS、TLR4等介导的天然免疫信号通路的激活，诱导炎性小体的形成，促进p53依赖的细胞凋亡和能量依赖性的细胞自噬，并在多种病毒感染中发挥抗病毒作用。IFI16发挥作用具有细胞特异性差异，它对巨噬细胞在DNA刺激下的有效感知和信号传导至关重要，从而能更迅速地启动干扰素和抗病毒免疫反应^[65]。除此之外，IFI16不同的亚细胞定位也可能对其发挥作用产生一定影响。在病毒感染或DNA转染时可调节IFI16在细胞质中的亚细胞定位，影响IFN的生成^[34,51]。此外，Huérfano等^[66]研究表明，紫外线处理上皮细胞后，IFI16从细胞核重新定位至细胞质，这可能与乳腺癌1号基因和受损DNA的监视与修复有关。IFI16蛋白的重新分布也与细胞凋亡有关。然而，目前关于调控IFI16蛋白在细胞核和细胞质间再分配的分子机制尚不清楚，可能受IFI16基因多态性、蛋白-蛋白相互作用和翻译后修饰等多种因素调控。

IFI16是一种独特的细胞传感器，不仅能识别各种形式的DNA，如dsDNA、ssDNA、HIV逆转录的中间体、超螺旋和十字型DNA等，还能与RIG-I、siRNA形成复合物。IFI16对于DNA、RNA的感知和基因组调控之间应存在更深层次的机制，这些问题仍有待进一步研究予以阐明。鉴于IFI16是先天免疫反应中参与DNA感知和基因调控的蛋白质之一，且可作为多种DNA病毒和RNA病毒的限制因子，因此有望成为治疗病毒感染的靶标分子。通过调节IFI16的表达水平或其介导的信号转导途径，可增强机体的免疫应答能力和清除外界病原体的能力，进而实现抗病毒感染的目标。然而，IFI16的异常表达与多种免疫相关疾病密切相关，其高表达状态与自身免疫性疾病、炎症相关疾病的发生发展存在一定相关性。因此，深入解析IFI16的结构与功能特点有助于阐明免疫相关疾病的发生机制，并为相关疾病的治疗提供新思路和新方法。

基金

收起

中央高校基本科研业务费专项资金(31920240125-01)
中央高校基本科研业务费专项资金(31920250002)
甘肃省自然科学基金(25JRRA048)
甘肃省高校教师创新基金(2025B-033)
国家自然科学基金(32260037)

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2026年第66卷第2期

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文章信息

doi: 10.13343/j.cnki.wsxb.20250365

接收时间：2025-05-06
首发时间：2026-02-05
出版时间：2026-02-04

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文章信息

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出版历史

收稿日期：2025-05-06
录用日期：2025-11-28

基金

the Fundamental Research Funds for the Central Universities(31920240125-01)

中央高校基本科研业务费专项资金(31920240125-01)

中央高校基本科研业务费专项资金(31920250002)

the Natural Science Foundation of Gansu Province(25JRRA048)

甘肃省自然科学基金(25JRRA048)

the Innovation Fund for University Teachers in Gansu Province(2025B-033)

甘肃省高校教师创新基金(2025B-033)

the National Natural Science Foundation of China(32260037)

国家自然科学基金(32260037)

作者信息

^1.西北民族大学，生物医学研究中心，细胞基质疫苗关键技术与产业化教育部工程研究中心，甘肃兰州

^2.西北民族大学，生物医学研究中心，甘肃省动物细胞技术创新中心，甘肃兰州

^3.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

^4.西北民族大学生命科学与工程学院，甘肃兰州

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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

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病毒 Viruses	功能 Function
单纯疱疹病毒1 Herpes simplex virus-1 (HSV-1)	非特异性结合并降低HSV-1基因组可及性以抑制感染^[57]；通过液-液相分离机制启动先天免疫信号并抑制HSV-1转录^[58]；与DNA-PK形成抗病毒信号轴，调控先天免疫应答^[59] Indiscriminately binds to and diminishes accessibility of the HSV-1 genome to suppress infection^[57]; initiates innate immune signaling through liquid-liquid phase separation and suppresses viral transcription^[58]; IFI16 and DNA-PK form an antiviral signaling axis that governs innate immunity to HSV-1 infection^[59]
爱泼斯坦-巴尔病毒 Epstein-barr virus (EBV)	与HCM核心组分协同作用，沉默EBV关键裂解开关蛋白，从而确保病毒在B淋巴细胞中持续处于潜伏状态^[8] Partners with core components of the HCM to silence the key EBV lytic switch protein, ensuring continued viral latency in B lymphocytes^[8]
人巨细胞病毒 Human cytomegalovirus (HCMV)	与ChREBP协同作用下调GLUT4的转录激活，减少HCMV诱导的脂肪合成酶转录，导致脂质合成减少，抑制病毒颗粒的从头形成^[45] Cooperates with ChREBP to downregulate GLUT4 transcriptional activation, reduces HCMV-induced transcription of lipogenic enzymes, leading to diminished lipid synthesis, and curbs the formation of viral particles^[45]
卡波氏肉瘤相关疱疹病毒 Kaposi’s sarcoma-associated herpesvirus (KSHV)	PAN RNA协助NAT10招募IFI16 mRNA，从而提高IFI16的翻译效率并诱导炎症小体的激活^[44]；招募HDAC1和HDAC2去乙酰化KSHV的LANA，维持病毒潜伏^[46] PAN RNA assists in NAT10 recruitment to IFI16 mRNA, resulting in increased IFI16 translation efficiency and inflammasome induction^[44]; recruits HDAC1 and HDAC2 to deacetylate LANA of KSHV, facilitating its latency^[46]
痘病毒 Vaccinia virus (VACV)	IFI16-iso1优先与细胞质复制的VACV共定位，诱导干扰素刺激基因的转录，激活抗病毒免疫反应；IFI16-iso2可清除入侵VACV^[16] IFI16-iso1 preferentially colocalizes with cytoplasm-replicating VACV, induces the transcription of IFN-stimulated genes, and elicits the antiviral immune response; IFI16-iso2 can clear invaded VACV^[16]
腺相关病毒2型 Adeno-associated virus type 2 (AAV2)	通过干扰Sp1介导的病毒启动子的反式激活，以一种与免疫调节无关的方式限制AAV2转导^[47] Restricts AAV2 transduction in an immune-modulatory independent way by interfering with SP1-mediated transactivation of the viral promoters^[47]
人乳头瘤病毒 Human papillomavirus (HPV)	通过促进HPV DNA异染色质化，抑制HPV18早期和晚期启动子活性，进而限制HPV的复制和基因表达^[48] Restricts HPV replication and gene expression by promoting the assembly of heterochromatin on HPV DNA and repressing the activities of both early and late HPV18 promoters^[48]
乙型肝炎病毒 Hepatitis B virus (HBV)	通过靶向cccDNA的ISRE，整合先天免疫激活与表观遗传调控，阻断HBV cccDNA的功能^[49] Inhibits the function of HBV cccDNA by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA^[49]
基孔肯雅病毒 Chikungunya virus (CHIKV)	通过与CHIKV基因组结合，以不依赖干扰素信号或DNA结合转录活性的方式抑制CHIKV复制^[50] Restricts CHIKV replication independent of interferon-signaling or DNA-binding transcriptional activity by binding to CHIKV genomes^[50]
尼帕病毒 Nipah virus (NiV)	识别泄漏至胞质中的线粒体DNA (mitochondrial DNA, mtDNA)，并主要通过激活STING/NF-κB信号及炎症因子反应，以控制NiV感染^[31] Recognizes mtDNA that leaks into the cytoplasm and primarily activates STING/NF-κB and inflammatory cytokines response to control NiV infection^[31]

病毒

Viruses

功能

Function

单纯疱疹病毒1

Herpes simplex virus-1 (HSV-1)

非特异性结合并降低HSV-1基因组可及性以抑制感染^[57]；通过液-液相分离机制启动先天免疫信号并抑制HSV-1转录^[58]；与DNA-PK形成抗病毒信号轴，调控先天免疫应答^[59]

Indiscriminately binds to and diminishes accessibility of the HSV-1 genome to suppress infection^[57]; initiates innate immune signaling through liquid-liquid phase separation and suppresses viral transcription^[58]; IFI16 and DNA-PK form an antiviral signaling axis that governs innate immunity to HSV-1 infection^[59]

爱泼斯坦-巴尔病毒

Epstein-barr virus (EBV)

与HCM核心组分协同作用，沉默EBV关键裂解开关蛋白，从而确保病毒在B淋巴细胞中持续处于潜伏状态^[8]

Partners with core components of the HCM to silence the key EBV lytic switch protein, ensuring continued viral latency in B lymphocytes^[8]

人巨细胞病毒

Human cytomegalovirus (HCMV)

与ChREBP协同作用下调GLUT4的转录激活，减少HCMV诱导的脂肪合成酶转录，导致脂质合成减少，抑制病毒颗粒的从头形成^[45]

Cooperates with ChREBP to downregulate GLUT4 transcriptional activation, reduces HCMV-induced transcription of lipogenic enzymes, leading to diminished lipid synthesis, and curbs the formation of viral particles^[45]

卡波氏肉瘤相关疱疹病毒

Kaposi’s sarcoma-associated herpesvirus (KSHV)

PAN RNA协助NAT10招募IFI16 mRNA，从而提高IFI16的翻译效率并诱导炎症小体的激活^[44]；招募HDAC1和HDAC2去乙酰化KSHV的LANA，维持病毒潜伏^[46]

PAN RNA assists in NAT10 recruitment to IFI16 mRNA, resulting in increased IFI16 translation efficiency and inflammasome induction^[44]; recruits HDAC1 and HDAC2 to deacetylate LANA of KSHV, facilitating its latency^[46]

痘病毒

Vaccinia virus (VACV)

IFI16-iso1优先与细胞质复制的VACV共定位，诱导干扰素刺激基因的转录，激活抗病毒免疫反应；IFI16-iso2可清除入侵VACV^[16]

IFI16-iso1 preferentially colocalizes with cytoplasm-replicating VACV, induces the transcription of IFN-stimulated genes, and elicits the antiviral immune response; IFI16-iso2 can clear invaded VACV^[16]

腺相关病毒2型

Adeno-associated virus type 2 (AAV2)

通过干扰Sp1介导的病毒启动子的反式激活，以一种与免疫调节无关的方式限制AAV2转导^[47]

Restricts AAV2 transduction in an immune-modulatory independent way by interfering with SP1-mediated transactivation of the viral promoters^[47]

人乳头瘤病毒

Human papillomavirus (HPV)

通过促进HPV DNA异染色质化，抑制HPV18早期和晚期启动子活性，进而限制HPV的复制和基因表达^[48]

Restricts HPV replication and gene expression by promoting the assembly of heterochromatin on HPV DNA and repressing the activities of both early and late HPV18 promoters^[48]

乙型肝炎病毒

Hepatitis B virus (HBV)

通过靶向cccDNA的ISRE，整合先天免疫激活与表观遗传调控，阻断HBV cccDNA的功能^[49]

Inhibits the function of HBV cccDNA by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA^[49]

基孔肯雅病毒

Chikungunya virus (CHIKV)

通过与CHIKV基因组结合，以不依赖干扰素信号或DNA结合转录活性的方式抑制CHIKV复制^[50]

Restricts CHIKV replication independent of interferon-signaling or DNA-binding transcriptional activity by binding to CHIKV genomes^[50]

尼帕病毒

Nipah virus (NiV)

识别泄漏至胞质中的线粒体DNA (mitochondrial DNA, mtDNA)，并主要通过激活STING/NF-κB信号及炎症因子反应，以控制NiV感染^[31]

Recognizes mtDNA that leaks into the cytoplasm and primarily activates STING/NF-κB and inflammatory cytokines response to control NiV infection^[31]