微生物学报

名称 Name	功能 Function	文献 References
AID	AID relies on loop7 in its structure, which is far away from the active center, to recognize the immunoglobulin single chain gene fragment 5′-WC-3′ (W=A/T, R=A/G) and exert C-to-U gene editing function	[14]
Editing the genome of viruses (such as hepatitis B virus) or deaminase independent mechanisms to inhibit virus replication	[15]
APOBEC1	APOBEC1 has a conserved zinc finger domain and deamination active site, and its N-terminus contains a nuclear localization signal that plays an important role in editing reactions and may participate in the binding of accessory proteins	[16]
Single mutants of L180, L182, I185, and L189, as well as double mutants of P190A/P191A, can all cause partial or almost complete loss of editing activity of APOBEC1	[17]
Specific editing of cytosine in ApoB 100 pre mRNA yields truncated ApoB48, ApoB 100 can transport endogenous cholesterol and triglycerides in the blood. ApoB48 plays a role in metabolizing dietary lipids	[18-19]
RBM46 can promote APOBEC1 to do the C-to-U editing of ApoB mRNA	[20]
Inducing DNA mutations or other mechanisms to inhibit certain viruses and reverse transcriptase elements	[21-22]
Promote polarization of M1 macrophages	[23-24]
Affects cancer genes or other pathological processes, such as, affects central nervous system lesions, APOBEC1 catalyzed C-to-U editing also exists in neurofibromas and lung adenocarcinoma	[25-27]
APOBEC2	Regulating and maintaining muscle development in mammals, leading to changes in muscle fiber subtypes, weight loss, and myopathy	[28-29]
Related to lung tumors, liver inflammation, and liver cancer	[30]
APOBEC3A	Specific deamination effect	[31]
Synergistic dimerization regulates the binding specificity of ssDNA	[32-33]
Responding to interferon-α in macrophages and monocytes, inhibiting viruses such as HIV-1, HPV, AAV, RSV, HTLV-1, etc.	[34-36]
During the polarization process of M1 macrophages, APOBEC3A mediates specific C to U RNA editing, thereby altering the amino acid sequences of proteins related to the pathogenesis of viral diseases and other large quantities of proteins	[37-38]
APOBEC3A exerts deamination ability by recognizing 5-methylcytosine (5mC), which is related to the clearance of viruses carrying CpG methylation	[39]
Editing the DNA of HeLa cells and U937 cells with Nox enzyme leads to ROS production, inducing the formation of pro-inflammatory state, which may be related to tumorigenesis	[40]
APOBEC3B	Effectively inhibit HIV-2 by relying on Vif	[41]
Human A3B has catalytic activity and inhibits HIV-1, while rhesus monkey A3B has no ability to inhibit HIV-1	[42]
DExD/H-box helicase 9 inhibits the binding of A3B to pgRNA and antagonizes the inhibitory effect of A3B on HBV	[43]
May be an important factor in inducing cancer mutations	[44-46]
Related to cell cycle deviation, cell death, DNA breakage, accumulation of γ-H2AX, and C to T transition	[47]
APOBEC3C	The antiviral function of A3CS188 dimer is significant	[48-49]
The inhibitory effect on HIV-1 is weak, but the anti-SIV function is strong. Simultaneously possessing the ability to inhibit viruses such as HSV-1, EBV, HBV, etc.	[50-53]
APOBEC3DE	Inhibition of HIV-1 and SIV virus replication	[54]
APOBEC3F	Inhibition of PERV and PRRSV replication	[55-56]
CAEV’s Vif induces degradation of sheep A3F and antagonizes the inhibitory effect of A3F on the virus	[57]
The driving factors of mutations in human monkeypox virus	[58]
A3F expression in cancer triple negative breast cancer is associated with tumor microenvironment invasion, activation of cancer immunity, and improved survival rate	[59]
APOBEC4	Participate in mouse spermatogenesis	[60]
Enhance HIV-1 production in a dose-dependent manner and have an effect on viral LTRs	[61]
Chicken APOBEC4 can inhibit the replication of NDV, IBDV, and H9	[62]

名称 Name	功能 Function	文献 References
AID	AID relies on loop7 in its structure, which is far away from the active center, to recognize the immunoglobulin single chain gene fragment 5′-WC-3′ (W=A/T, R=A/G) and exert C-to-U gene editing function	[14]
Editing the genome of viruses (such as hepatitis B virus) or deaminase independent mechanisms to inhibit virus replication	[15]
APOBEC1	APOBEC1 has a conserved zinc finger domain and deamination active site, and its N-terminus contains a nuclear localization signal that plays an important role in editing reactions and may participate in the binding of accessory proteins	[16]
Single mutants of L180, L182, I185, and L189, as well as double mutants of P190A/P191A, can all cause partial or almost complete loss of editing activity of APOBEC1	[17]
Specific editing of cytosine in ApoB 100 pre mRNA yields truncated ApoB48, ApoB 100 can transport endogenous cholesterol and triglycerides in the blood. ApoB48 plays a role in metabolizing dietary lipids	[18-19]
RBM46 can promote APOBEC1 to do the C-to-U editing of ApoB mRNA	[20]
Inducing DNA mutations or other mechanisms to inhibit certain viruses and reverse transcriptase elements	[21-22]
Promote polarization of M1 macrophages	[23-24]
Affects cancer genes or other pathological processes, such as, affects central nervous system lesions, APOBEC1 catalyzed C-to-U editing also exists in neurofibromas and lung adenocarcinoma	[25-27]
APOBEC2	Regulating and maintaining muscle development in mammals, leading to changes in muscle fiber subtypes, weight loss, and myopathy	[28-29]
Related to lung tumors, liver inflammation, and liver cancer	[30]
APOBEC3A	Specific deamination effect	[31]
Synergistic dimerization regulates the binding specificity of ssDNA	[32-33]
Responding to interferon-α in macrophages and monocytes, inhibiting viruses such as HIV-1, HPV, AAV, RSV, HTLV-1, etc.	[34-36]
During the polarization process of M1 macrophages, APOBEC3A mediates specific C to U RNA editing, thereby altering the amino acid sequences of proteins related to the pathogenesis of viral diseases and other large quantities of proteins	[37-38]
APOBEC3A exerts deamination ability by recognizing 5-methylcytosine (5mC), which is related to the clearance of viruses carrying CpG methylation	[39]
Editing the DNA of HeLa cells and U937 cells with Nox enzyme leads to ROS production, inducing the formation of pro-inflammatory state, which may be related to tumorigenesis	[40]
APOBEC3B	Effectively inhibit HIV-2 by relying on Vif	[41]
Human A3B has catalytic activity and inhibits HIV-1, while rhesus monkey A3B has no ability to inhibit HIV-1	[42]
DExD/H-box helicase 9 inhibits the binding of A3B to pgRNA and antagonizes the inhibitory effect of A3B on HBV	[43]
May be an important factor in inducing cancer mutations	[44-46]
Related to cell cycle deviation, cell death, DNA breakage, accumulation of γ-H2AX, and C to T transition	[47]
APOBEC3C	The antiviral function of A3CS188 dimer is significant	[48-49]
The inhibitory effect on HIV-1 is weak, but the anti-SIV function is strong. Simultaneously possessing the ability to inhibit viruses such as HSV-1, EBV, HBV, etc.	[50-53]
APOBEC3DE	Inhibition of HIV-1 and SIV virus replication	[54]
APOBEC3F	Inhibition of PERV and PRRSV replication	[55-56]
CAEV’s Vif induces degradation of sheep A3F and antagonizes the inhibitory effect of A3F on the virus	[57]
The driving factors of mutations in human monkeypox virus	[58]
A3F expression in cancer triple negative breast cancer is associated with tumor microenvironment invasion, activation of cancer immunity, and improved survival rate	[59]
APOBEC4	Participate in mouse spermatogenesis	[60]
Enhance HIV-1 production in a dose-dependent manner and have an effect on viral LTRs	[61]
Chicken APOBEC4 can inhibit the replication of NDV, IBDV, and H9	[62]

APOBEC家族蛋白的结构功能及其在疾病控制中的作用

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张志杰 ¹^,² , 王松祺 ¹^,³ , 聂晶晶 ¹ , 瞿云芝 ¹ , 沈海燕 ¹

微生物学报 | 综述 2025,65(5): 1849-1866

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微生物学报 | 综述 2025, 65(5): 1849-1866

APOBEC家族蛋白的结构功能及其在疾病控制中的作用

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张志杰¹^,², 王松祺¹^,³, 聂晶晶¹, 瞿云芝¹, 沈海燕¹

作者信息

^1.广东省农业科学院动物卫生研究所，广东省畜禽疫病防治研究重点实验室，广东广州

^2.西北农林科技大学动物医学院，陕西杨凌

^3.华南农业大学兽医学院，广东广州

Structures and functions of APOBEC family members and their roles in disease control

Zhijie ZHANG¹^,², Songqi WANG¹^,³, Jingjing NIE¹, Yunzhi QU¹, Haiyan SHEN¹

Affiliations

^1.Key Laboratory of Livestock Disease Prevention of Guangdong Province, Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangzhou, Guangdong, China

^2.College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China

^3.College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong, China

出版时间: 2025-05-04 doi: 10.13343/j.cnki.wsxb.20240673

文章导航

摘要

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活化诱导胞苷脱氨酶(activation-induced cytidine deaminase, AID)和载脂蛋白B mRNA编辑酶催化多肽(apolipoprotein B mRNA-editing enzyme, catalytic polypeptide, APOBEC)构成了一类保守的胞苷脱氨酶家族，各成员蛋白在机体内发挥着各不相同的功能，并且在机体的天然免疫防御机制中也发挥着重要作用。AID在脊椎动物的获得性免疫系统中发挥重要作用，其介导抗体类别转换重组(class switch recombination, CSR)、促进抗体亲和力成熟，并参与抗体多样性的产生。APOBEC1则具有催化胞嘧啶脱氨基化、介导RNA编辑以调控细胞功能的作用，同时还展现出抗逆转录病毒活性，并与肿瘤和癌症的发生存在一定的关联。APOBEC2主要在心肌和骨骼肌中表达，与肌肉纤维类型的转变、体重下降、肌肉再生以及体细胞肌肉组织相关疾病有关，同时在控制基因表达方面也具有潜在作用。APOBEC3s在天然免疫和获得性免疫应答中均占据重要地位，其成员蛋白在抑制逆转录转座子、抑制病毒复制、DNA降解、RNA编辑以及影响细胞周期等方面均发挥着关键作用。APOBEC4基因在各种动物中相对保守，其活性中心序列与其他APOBEC蛋白不同，是公认的胞苷对尿苷编辑酶，并具有抗病毒活性。目前，关于动物源APOBEC家族成员的研究相对较少，本文综述了APOBEC家族成员的结构特征和生物功能，为日后研究动物源APOBEC家族成员在机体免疫应答及对疾病影响方面提供参考，同时也为进一步探索利用增强APOBEC家族成员功能的活性物质来寻找抗病毒药物提供新思路。

关键词

载脂蛋白B mRNA编辑酶催化多肽(APOBEC) / 活化诱导的胞苷脱氨酶 / APOBEC3s / 生物功能

Abstract

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Activation induced cytidine deaminase (AID) and apolipoprotein B mRNA editing enzyme catalytic peptide (APOBEC) constitute a conserved family of cytidine deaminase enzymes. The family members have different functions in the body, and they play an important role in the immune defense of the host. AID plays a role mainly in the adaptive immune systems of vertebrates, mediating class switch recombination, antibody affinity maturation, and antibody diversity generation. APOBEC1 capable of catalyzing cytosine deamination, mediating RNA editing for cellular regulation, and resisting retroviral infection is involved in tumorigenesis and cancer development. APOBEC2, most abundant in cardiac and skeletal muscle, is associated with muscle fiber type switch, loss of weight, muscle development, and myopathy. Moreover, it may have potential indirect effects in controlling gene expression. APOBEC3s play key roles in both innate and adaptive immune responses. They are involved in the inhibition of retrotransposon functioning and viral infection, DNA degradation, RNA editing, and cell cycle regulation. The APOBEC4 gene is conserved in various animal species, with the active center sequence different from those of other APOBEC proteins. It is widely recognized that APOBEC4 is a uridine-editing enzyme, which has antiviral activity. The research is limited regarding the animal-derived APOBEC family members. This review describes the structural characteristics and biological functions of APOBEC family members, providing reference for research on the roles of animal-derived APOBEC family members in the immune responses and disease control. In addition, this review provides new ideas for the development of antivirals by enhancing the activities of APOBEC family members.

Key words

apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) / activation-induced cytidine deaminase (AID) / APOBEC3s / biologic function

引用本文

张志杰, 王松祺, 聂晶晶, 瞿云芝, 沈海燕. APOBEC家族蛋白的结构功能及其在疾病控制中的作用. 微生物学报, 2025 , 65 (5) : 1849 -1866 . DOI: 10.13343/j.cnki.wsxb.20240673

Zhijie ZHANG, Songqi WANG, Jingjing NIE, Yunzhi QU, Haiyan SHEN. Structures and functions of APOBEC family members and their roles in disease control[J]. Acta Microbiologica Sinica, 2025 , 65 (5) : 1849 -1866 . DOI: 10.13343/j.cnki.wsxb.20240673

正文

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APOBEC家族是一个庞大的体内家族，其成员具有脱氨酶活性，包括活化诱导胞苷脱氨酶(activation-induced cytidine deaminase, AID)、载脂蛋白B mRNA编辑酶催化多肽-1 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide, APOBEC1)、APOBEC2、APOBEC3 (简称A3，包含A3A、A3B、A3C、A3DE、A3F、A3G、A3H)和APOBEC4亚家族，共计11个成员^[1]。APOBEC家族蛋白作为机体内关键的宿主蛋白，在抵抗病毒感染和激发免疫应答中发挥重要作用^[2]。随着研究的深入，APOBEC家族成员在不同方面的功能逐渐被揭示。APOBEC家族成员不仅在机体获得性免疫中发挥重要的功能，而且在天然免疫中也同样具有不可或缺的作用^[3]。Feng等^[4]研究发现，AID通过将DNA胞嘧啶脱氨基成尿嘧啶来启动体细胞超突变(somatic hypermutation, SHM)和抗体类别转换重组(class switch recombination, CSR)。APOBEC1则能够使哺乳动物的体内的RNA脱氨基^[5]；APOBEC3s蛋白不仅能够抑制DNA病毒和RNA病毒的复制，对反转录病毒的增殖同样具有阻碍作用，而且还能影响反转录元件的移动^[6-7]，因此在天然免疫系统中发挥重要作用。此外，研究发现APOBEC3亚家族成员可通过诱导驱动突变和调节肿瘤免疫微环境来影响肿瘤进化，在癌症类型中具有不同的预后意义，并在当前和未来临床治疗中发挥重要作用^[8]。相比之下，对于APOBEC2和APOBEC4的功能研究相对较少。

APOBEC家族成员的胞苷脱氨酶功能区(catalytic domains, CD)含有特异性的锌指结构域(His-X-Glu-X_23-28-Pro-Cys-X_2-4-Cys，其中X表示任意氨基酸)，是该家族成员保守的酶活性中心(图1)^[9]。根据所含脱氨基酶结构域数量的不同，APOBEC家族成员可分为2类：一类是AID、APOBEC1、A3A、A3C、A3H蛋白，仅包含单个结构域；另一类是A3B、A3DE、A3F和A3G，包含2个结构域^[9]。APOBEC家族成员通过识别靶基因的特异性核酸位点发挥脱氨基和编辑作用，例如APOBEC3B和APOBEC3F主要在3′-CC和3′-TC的二联核苷酸序列处发生编辑作用^[3,10]。此外，根据APOBEC3家族成员相对保守的氨基酸基元序列，又可将其分为Z1 (A3A、A3B-CD2、A3G-CD2)、Z2 (A3B-CD1、A3C、A3DE、A3F、A3G-CD1)和Z3 (A3H) 3类(图2)。在啮齿类动物中，A3基因座包含1个A3基因；在猪中包含2个；在马中包含6个；在猫中包含4个^[10-12]。人类/灵长类动物的A3命名法遵循最初提出的系统(A3A-A3H)，而非灵长类动物的A3新命名法则是基于Z结构域的存在与否而提出的^[13]。

本文对APOBEC家族各成员的结构和生物学功能在国内外的研究进展进行了综述(表1)，旨在为日后动物源APOBEC家族成员功能的研究及其在疾病发生后的免疫反应中作用机制的揭示提供方向，同时也为以增强APOBEC家族成员功能的活性为靶点研发新型抗病毒药物奠定基础。

1 AID的结构和生物功能

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AID含有核定位信号和依赖运输蛋白(chromosome region maintenance 1, CRM1)的核输出信号(图3)，AID能够与真核延伸因子1α、热休克蛋白90以及可能的RNA相互作用，进而停留在细胞质中^[9]。AID的结构包含6个α螺旋和5个β折叠，在转录过程中，它通过识别免疫球蛋白单链基因片段5′-WRC-3′ (W=A/T，R=A/G)并发挥C-to-U基因编辑的功能，这一功能依赖于远离活性中心的loop7^[14]。

作为DNA编辑酶，AID通过调控免疫球蛋白基因位点、启动抗体类性别转换重组(CSR)和体细胞超突变(SHM)，影响B细胞的多样化^[4]。此外，AID还能通过编辑病毒(如乙型肝炎病毒)基因组或脱氨酶非依赖性机制来抑制病毒复制^[15]。研究还发现，缺失外显子4的AID剪接突变体与CRM1和真核翻译延伸因子1A (eukaryotic translation elongation factor 1A, eEF1A)结合，在AID活性和癌症失调中发挥作用^[9]。因此，AID活性调节在B细胞肿瘤发展中的免疫球蛋白基因表达和c-Myc致癌基因易位中起着关键作用^[9]。

2 APOBEC1的结构和生物功能

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APOBEC1具有保守的锌指结构域和脱氨基活性位点，其N端包含对编辑反应具有重要作用的核定位信号，并可能参与辅助蛋白的结合^[16]；C端180-196 aa是保守的亮氨酸富集区域(图4)，Teng等^[17]研究表明L180、L182、I185和L189的单突变体，以及P190A/P191A双突变体，均能导致APOBEC1的编辑活性部分或几乎完全丧失。

APOBEC1能特异性编辑ApoB 100 pre-mRNA内的胞嘧啶，产生1个新的终止密码子，从而得到ApoB蛋白的截短体ApoB 48，其中，ApoB 100负责运输血液中的内源性胆固醇和甘油三酸酯，但这一作用有导致动脉粥样硬化的风险^[18]，而ApoB48在代谢膳食脂类中发挥作用，对降低动脉粥样硬化风险具有重要作用^[19]。APOBEC1介导的单胞嘧啶脱氨基作用需要与辅助蛋白APOBEC1互补因子(APOBEC1 complementation factor, A1CF)或RNA结合模体蛋白-47 (RNA binding motif, RBM47)形成RNA编辑活性的 “编辑体”^[16]。此外，Wang等^[20]还发现新的辅因子RBM46可以促进APOBEC1对ApoB mRNA的C-to-U编辑。除了RNA编辑活性外，APOBEC1还能通过诱导DNA突变^[21]或其他机制抑制某些病毒和逆转录酶元件^[22]。

APOBEC1对肠上皮细胞系、树突状细胞和巨噬细胞等多种细胞具有RNA编辑作用^[23]。茹福霞^[24]的研究发现，APOBEC1可通过其RNA编辑功能影响IL-12b的3ʹ-UTR与RBP结合，阻碍蛋白复合物形成，从而上调IL-12b等表达水平，促进M1型巨噬细胞的极化。此外，Rosenberg等^[25]研究发现，APOBEC1通过编辑细胞因子mRNA 3′-端非翻译区域胞嘧啶位点的功能，影响癌症基因或其他病理过程。例如，溶酶体膜蛋白2的mRNA被APOBEC1编辑后，出现溶酶体表达异常，导致中枢神经系统病变^[26]；在神经纤维瘤以及肺腺癌中也存在APOBEC1催化的C-to-U编辑情况^[27]。

3 APOBEC2的结构和生物功能

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在EST数据库中搜索时发现了与APOBEC1同源的基因APOBEC2，对全长APOBEC2核磁结构的解析发现其在溶液中呈单体状态，且N端与APOBEC2的聚集状态有关^[63]。此外，还发现N端40个氨基酸被剪切的截短体蛋白的晶体结构，形成了头对头方式相互作用的棒状四聚体结构(图5)^[64]。

Li等^[28]研究发现，APOBEC2定位于发育中的心肌和骨骼肌纤维的细胞核，在哺乳动物的肌肉发育中起着重要的调节和维持作用。Sato等^[29]指出，如果APOBEC2发生异常表达，则会导致肌肉纤维亚型的转变、体重减轻和肌病。在斑马鱼胚胎中，APOBEC2蛋白是肌隔膜完整性和通过Hsp90a非依赖性途径附着肌纤维所必需的^[65]。在鸡的骨骼肌和心肌中，APOBEC2 mRNA的表达最为丰富，而在皮下脂肪组织、性腺和胃中的表达相对较低^[28]。Pennings等^[66]发现APOBEC2可能在转录水平上发挥作用，在早期干细胞分化过程中上调，并在非洲爪蟾中胚层的表达与左右体轴的有序发育相关。此外，Li等^[28]还发现，在APOBEC2启动子中存在一个对肌源性调节因子MyoD高亲和力的结合位点，该位点在包括鱼类、鸟类、啮齿类动物和人类在内的多种动物物种中都是保守的，这表明APOBEC2基因表达可能受MyoD调节，并可能进一步调节肌源性发育。

在心脏组织中，人源APOBEC2可能具有特定的作用，APOBEC2的过表达与肝癌和肺肿瘤有关，可能引发磷酸酶的基因和编码真核翻译起始因子4γ2的突变^[9]。Matsumoto等^[30]指出，在人类肝细胞中，促炎细胞因子通过激活核因子κB (nuclear factor kappa-B, NF-κB)调节APOBEC2表达，并且APOBEC2可能在肝脏炎症的病理生理学中发挥作用。

4 APOBEC3的结构和生物功能

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4.1 APOBEC3A

人类APOBEC3A包含一个脱氨酶域，其中半胱氨酸(cysteine, Cys)和组氨酸(histidine, His)与锌离子协调作用，而谷氨酸(glutamic acid, Glu)则在催化过程中的质子转移中发挥关键作用。APOBEC3A蛋白具有专一性的脱氨基作用，其对含TC的单链DNA上Ｃ碱基的作用取决于底物核苷酸的侧面序列(图6)^[31]。此外Bohn等^[32]发现，APOBEC3A的二聚化调控着单链DNA (single-stranded DNA, ssDNA)的结合特异性，可将ssDNA底物上的MeC脱氨基成为T，C脱氨基成为U^[33]。APOBEC3A能够抑制多种病毒，包括人类免疫缺陷病毒-1 (human immunodeficiency virus 1, HIV-1)、人乳头瘤病毒(human papilloma virus, HPV)、腺相关病毒(adeno-associated virus, AAV)、呼吸道合胞病毒(respiratory syncytial virus, RSV)和人类嗜T淋巴细胞病毒1型病毒(human T-cell lymphotropic virus, HTLV-1)^[34-35]。在应答干扰素-α时，APOBEC3A在巨噬细胞和单核细胞中大量表达^[36]。在巨噬细胞M1极化过程中，APOBEC3A介导特异性的C-to-U RNA编辑，从而改变与病毒性疾病发病过程相关的蛋白^[37]。Kim等^[38]研究显示，APOBEC3A、APOBEC1和APOBEC3G能够使严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) RNA中的特定位点产生C-to-U突变；然而，在Caco-2细胞中，这些APOBECs的表达并不抑制SARS-CoV-2的复制和病毒子代的产生；相反地，野生型APOBEC3s的表达极大地促进了SARS-CoV-2的复制/繁殖，这表明SARS-CoV-2利用了APOBEC介导的突变进行适应和进化。此外，APOBEC3A通过识别5-甲基化胞嘧啶(5-methylcytosine, 5mC)发挥脱氨基能力，这与清除携带CpG甲基化的病毒有关^[39]。APOBEC3A还可以通过Nox酶编辑HeLa细胞和U937细胞的DNA导致活性氧(reactive oxygen species, ROS)的产生，从而诱导促炎状态的形成，这可能与致瘤性有关^[40]。

4.2 APOBEC3B

APOBEC3B主要位于细胞核，并能够在细胞质与细胞核之间穿梭^[67]。APOBEC3B以依赖病毒感染因子(viral infectivity factor, Vif)的方式有效抑制HIV-2^[41]。此外，APOBEC3B氨基酸序列的差异对其催化酶活性的影响十分关键。例如，人类APOBEC3B的第316位氨基酸是D，具有催化活性且能够抑制HIV-1；而在恒河猴的APOBEC3B中，该位置316位氨基酸是N，且不具有抑制HIV-1的能力^[42]。Chen等^[43]的研究还发现，DExD/H-box解旋酶9 (DExH-box helicase 9, DHX9)能够阻碍APOBEC3B与前基因组RNA (pre-genome RNA, pgRNA)的结合，从而拮抗APOBEC3B对乙型肝炎病毒(hepatitis B virus, HBV)的抑制作用。在乳腺癌、肺癌等肿瘤组织中，APOBEC3B过量表达，尽管具体机制尚不清楚，但被认为是诱发癌症突变的重要因素^[44-46]。此外，细胞周期紊乱和细胞死亡也与APOBEC3B的过量表达有关，APOBEC3B还在DNA断裂、γ-H2AX积聚及C to T突变中发挥着重要作用^[47]。

4.3 APOBEC3C

人类APOBEC3C的S188单体对HIV-1的抑制作用较弱，但I188单体的酶活性较强，且能显著增强对HIV-1的抑制能力，此外还发现A3C S188的二聚体具有显著的抗病毒功能，甚至高于A3C I188^[48-49]。尽管APOBEC3C对人类免疫缺陷病毒HIV-1的抑制作用相对较弱，但它对Vif缺陷的猴免疫缺陷病毒因子猴免疫缺陷病毒(simian immunodeficiency virus, SIV)却展现出强大的抑制功能^[50]。Sheehy等^[51]发现，灵长类APOBEC3C与Vif相结合，并在正选择压力下进化，这表明APOBEC3C在抵御病毒感染中发挥着重要作用，是病毒在天然感染过程中必须对抗的关键屏障。此外，APOBEC3C的过表达降低了HeLa细胞中HSV-1的病毒滴度和感染性，而且在感染外周单核细胞时，传染性单核细胞增多症病毒(epstein-Barr virus, EBV)的DNA存在被APOBEC3C编辑的现象^[52]。Li等^[53]还发现，细胞内和细胞培养上清中的HBV复制也被APOBEC3C显著抑制。此外，APOBEC3C还可以抑制non-LTR逆转录元件、长散在核元件(long-interspersednuclear element, LINE-1，简称L1)和Alu元件，尤其对L1和Alu的抑制作用更为显著^[39]。

4.4 APOBEC3DE

在非允许型细胞中APOBEC3DE大量表达，并能抑制HIV-1和SIV病毒的复制，但其活性比APOBEC3G和APOBEC3F弱。此外，人与黑猩猩的APOBEC3DE氨基酸序列存在显著差异，黑猩猩的APOBEC3DE对免疫型病毒HIV-1和SIV的感染具有限制作用，而人APOBEC3DE仅对HIV-1表现出较弱的抗病毒活性^[54]。

4.5 APOBEC3F

APOBEC3F的mRNA全长2 672 bp，编码框为1 122 bp，编码373个氨基酸^[68]，是人类细胞编码的具有HIV抗性的基因。APOBEC3F可以诱导反转录病毒cDNA双链核苷酸中的5′-TC胞嘧啶发生脱氨基化，导致DNA负链5′-TC突变为TT，而APOBEC3G则特异性地脱氨基化5′-CC中的3′端胞嘧啶；这2种反应都会产生尿嘧啶，进而引发DNA负链5′-CC到CT的突变^[69]。Dörrschuck等^[55]的研究显示，猪5号染色体上存在APOBEC3基因，由2个单结构域基因A3Z2和A3Z3组成，编码出4种不同的mRNA：A3Z2、A3Z3、A3Z2-Z3 (即APOBEC3F)和A3Z2-Z剪接变异体；进一步研究发现，猪APOBEC3具有抗猪内源性逆转录病毒(porcine endogenous retrovirus, PERV)和小鼠白血病病毒(murine leukemia viruses, MuLV)的活性；猪A3Z2、A3Z3和A3Z2-Z3被包装到PERV颗粒中，并以剂量依赖的方式抑制PERV复制，而且这种抗逆转录病毒的作用与猪APOBEC3s的编辑活性相关，A3Z2和A3Z2-Z3的核苷酸编辑活性偏好为5′-TGC，A3Z3的偏好为5′-CAC^[55,70]。Jónsson等^[70]的研究显示，PERV可能对猪APOBEC3F有一定的拮抗作用。此外，在Marc145细胞中过表达APOBEC3F可剂量依赖性地抑制猪繁殖与呼吸综合征病毒(porcine reproductive and respiratory syndrome virus, PRRSV) 的增殖，而当干扰内源性APOBEC3F时，则会促进PRRSV的增殖^[56]。此外，山羊关节炎脑炎病毒(caprine arthritis-encephalitis virus, CAEV)编码的Vif可以诱导绵羊A3Z2-Z3 (oaA3Z2-Z3)的降解来拮抗抑制病毒的作用^[57]。Suspène等^[58]的研究表明，APOBEC3F是2022年暴发的人类猴痘病毒的突变驱动因素。在癌症方面，APOBEC3F在三阴性乳腺癌中的表达与肿瘤微环境浸润、癌症免疫激活和提高生存率相关^[59]。

沈海燕等^[71]以猪小肠上皮细胞IPEC-J2为扩增模板，通过一步法RT-PCR扩增获得猪A3Z2基因的编码序列(coding sequence, CDS)区，遗传进化分析发现，猪A3Z2与人、牛、马、羊、猕猴、猫、小鼠和褐家鼠的APOBEC3位于同一个亚支；生物信息学分析显示，猪A3Z2为不稳定蛋白，编码280个氨基酸，其中精氨酸含量最多，蛋氨酸含量最少；猪A3Z2蛋白中有3个N-糖基化位点和26个磷酸化位点，不存在跨膜区和信号肽切割位点；预测结果表明，猪A3Z2蛋白的二级结构以α-螺旋为主；在A3Z2稳定表达的IPEC-J2-A3Z2细胞株中猪流行性腹泻病毒(porcine epidemic diarrhea virus, PEDV)的增殖被显著抑制，提示猪A3Z2是限制PEDV复制的宿主因子之一。

4.6 APOBEC3G

人类APOBEC3G基因由7个内含子和8个外显子组成，cDNA长1 155 bp，可翻译出384个氨基酸，蛋白大小约为46 kDa (图7)^[72]。Yang等^[73]研究发现APOBEC3G具有胞嘧啶脱氨作用，从而发挥抗HIV-1病毒的作用。APOBEC3G不仅能通过非胞嘧啶脱氨依赖的方式抗HIV-1，而且A3G可以与HIV-1整合酶相互作用，抑制前病毒DNA的形成^[74]。此外，APOBEC3G还能与HIV-1的逆转录酶相互作用，从而抑制HIV-1的活性^[75]。相反地，HIV-1编码的Vif蛋白对APOBEC3G具有拮抗作用，导致泛素化的APOBEC3G被蛋白酶体降解^[76]。此外，当APOBEC3G的功能区被Vif结合后，会阻碍其包装和进入病毒颗粒^[77]，或者Vif蛋白可能抑制APOBEC3G基因转录后的表达和蛋白合成^[78]。

同时，APOBEC3G还具有抑制SIV、HTLV、马传染性贫血病毒(equine infectious anaemia, EIAV)、MuLV以及泡沫病毒等多种逆转录病毒的作用^[79]。与HIV相似，小鼠APOBEC3G (mA3G)与Gag蛋白的结合会被MuLV病毒RNA阻断，导致mA3G被清除；或者在MLV病毒颗粒成熟后，小鼠mA3G蛋白会被病毒蛋白酶降解^[80]。Wang等^[81]发现A3G与肠道病毒71型(enterovirus 71, EV71)的RNA依赖性RNA聚合酶(RNA-dependent RNA polymerase, RdRp)及病毒RNA相互作用，并被包装到子代病毒中，从而降低EV71的传染性。此外，A3G还可以通过与多聚胞嘧啶结合蛋白1 (poly C binding protein-1, PCBP1)竞争结合5′-UTR，进而限制EV71 RNA的合成和病毒蛋白的翻译^[82]。相反，EV71能够通过诱导细胞自噬作用来拮抗A3G蛋白的抗病毒作用，从而逃逸宿主的天然免疫^[82]。

此外，APOBEC3G还能抑制HBV和丙型肝炎病毒(hepatitis C virus, HCV)的感染。外源表达的APOBEC3G蛋白可以显著降低HBV核相关DNA和RNA的水平^[83]，并且A3G能诱导HBV的共价闭合环状DNA分子(covalently closed circular DNA, cccDNA)发生超突变^[84]。在HBV感染的早期阶段，病毒DNA的合成会以非编辑依赖的方式被APOBEC3G抑制^[85]；同时，HBV的逆转录酶和RNA包装信号ε会与APOBEC3G相互作用并被包装进HBV核衣壳，从而发挥抑制病毒的作用^[86]。此外，HBV core蛋白也能直接与APOBEC3G作用，进入HBV病毒颗粒的包装过程，阻碍HBV衣壳蛋白的形成，进而影响HBV core蛋白对pgRNA的包装，干扰HBV的生命周期^[87]。Komohara等^[88]对HCV患者体内的APOBEC3G进行分析时发现，与非感染者相比，IFN-α作用后APOBEC3G的表达量升高，提示APOBEC3G可能参与了宿主抵抗HCV感染的过程。后续研究进一步证实，外源性APOBEC3G可以剂量依赖性地抑制HCV复制，并且APOBEC3G会被包装到HCV感染性子代病毒颗粒中，表明APOBEC3G是宿主细胞内拮抗HCV复制的限制性因子^[89]。

Fehrholz等^[90]对于APOBEC3G与其他病毒的研究发现，APOBEC3G能够抑制麻疹病毒(measles virus, MV)、腮腺炎病毒(mumps virus, MuV)及呼吸道合胞病毒(respiratory syncytial virus, RSV)的复制，而且A3G的过表达可以减少RSV的复制和合胞体的形成^[91]。Shichijo等^[92]发现HTLV-1易受hA3G的影响，hA3G可通过激活TGF-β/Smad (transforming growth factor-β/Smad)通路促进感染细胞的增殖，同时病毒中的反义因子通过A3G控制宿主细胞功能，这与疾病发病机制有关。Esnault等^[93]发现APOBEC3G可在长末端重复结构(long terminal repeat, LIR) DNA上发生G to A超突变，从而阻断逆转录转座作用的发生。Dutko等^[94]发现，在酵母细胞中APOBEC3G能诱导Ty1的DNA发生G to A突变，从而阻断Ty1的逆转录转座作用。此外，Chiu等^[95]研究表明，虽然人APOBEC3G对LINE-1的转座无显著抑制作用，但它可以抑制LINE-1参与的Alu和hY的逆转录转座。

4.7 APOBEC3H

人类APOBEC3H基因位于22q13.1，编码6个外显子^[96]。APOBEC3H具有单核苷酸多态性(single nucleotide polymorphisms, SNPs)，分别为N15Δ、R18L、R105G、K121D和E178D，这些多态性导致使APOBEC3H产生不同的突变体。APOBEC3H不同的单倍型在人类外周血、单核细胞，以及肝脏和皮肤等不同组织中均能检测到^[97]，这些单倍型被命名为Hap Ⅰ (NRGKE)、Hap Ⅱ (NRRDD)、Hap Ⅲ (ΔRRDD)、HapⅣ(ΔLRDD)、HapⅤ (NRRDD)、HapVI (ΔLGKD)和HapⅦ (NRRKE)^[2]。APOBEC3H HapⅢ和HapⅣ中的SNP ΔN15导致它们不能与RNA结合，而APOBEC3H HapⅡ Δ15N也无法通过被包装入HIV-1病毒粒子来发挥抗病毒作用^[2,98]。

APOBEC3H具有显著的抗病毒功能^[99]，APOBEC3H可以通过脱氨酶依赖和非依赖性的机制来对抗HIV-1^[100]。此外，Zhu等^[101]发现，APOBEC3H外显子2的rs139293 T等位基因与肺癌发病率的降低有关。因此，对APOBEC3H结构和功能特点的研究，可能为治疗癌症、艾滋病等疾病提供新的思路和方法。

5 APOBEC4的结构和生物功能

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APOBEC4是通过计算机同源搜索技术发现的，并确定了其位于人类1号染色体上的位置，APOBEC4基因在黑猩猩、恒河猴、狗、牛、小鼠、大鼠、鸡和青蛙等物种中是保守的^[60]。与其他APOBEC蛋白明显不同，APOBEC4的活性中心序列为Pro-Cys-X6-Cys^[60]。目前，关于APOBEC4的研究成果相对较少。尽管APOBEC4被公认为胞苷对尿苷的编辑酶，但在酵母和细菌中表达时并未展现出脱氨基活性^[102]。小鼠睾丸中APOBEC4基因的表达可能与精子发生过程有关^[60]。Marino等^[61]在293T细胞体系中共表达了APOBEC4与HIV-1，结果发现APOBEC4不仅不抑制HIV-1的复制，反而以剂量依赖的方式增强了HIV-1的产生，且似乎对病毒的长末端重复序列(long terminal repeat, LTR)起作用；APOBEC4在体外并未显示出可检测的胞苷脱氨活性，并且与单链DNA的相互作用较弱。鸡的APOBEC4能够抑制新城疫病毒(newcastle disease virus, NDV)、鸡传染性支气管炎病毒(infectious bronchitis virus, IBDV)和H9亚型禽流感病毒(H9 subtype avian influenza virus, H9-AIV)的复制，且这种抑制作用具有剂量依赖性。鸡APOBEC4不是通过RNA编辑依赖的作用方式，而是通过与辅助ADAR家族蛋白的相互作用来抑制病毒功能^[62]。

6 总结与展望

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AID/APOBEC家族蛋白具有细胞脱氨酶活性，其对底物的选择和催化脱氨的调节受与催化位点相邻的蛋白质结构域的长度、组成和空间排列的控制。APOBEC脱氨酶基因的表达失调和突变会导致DNA和mRNA序列的大量变化，进而引发多种免疫系统疾病(如高IgM综合征)以及恶性肿瘤(如B细胞淋巴瘤、肝细胞癌等)^[103]。AID脱氨酶通过在基因组DNA中引入突变来改变细胞表型，参与B淋巴细胞免疫球蛋白位点VDJ重组的体细胞高突变、抗体同种型转换和B细胞亲和力成熟过程^[104]。B细胞中AID的激活通常由B细胞受体在共刺激分子CD40、TLR或影响抗体类别选择的细胞因子[如白细胞介素-4 (interleukin 4, IL-4)、转化生长因子β (transforming growth factor-β, TGF-β)或干扰素-γ (interferon-γ, IFN-γ)]的额外信号背景下触发^[105]。触发AID表达的主要转录因子包括NF-κB和HoxC4^[105]。因此，鉴于其对表观遗传调控的贡献，AID被视为一把双刃剑：一方面，它有助于实现更可变的遗传密码，促进进化，建立中枢B细胞耐受性，并激发有效的体液反应；另一方面，它也增加了突变负荷，可能在致癌过程中发挥作用。鉴于这些发现，严格调控AID的表达和功能至关重要。未来对AID调节潜在机制的研究将为揭示导致各种病理结果的失调机制铺平道路，如克隆内异质性增加、自身免疫性疾病、免疫缺陷综合征、淋巴瘤和其他癌症，这些研究有可能带来新的治疗选择和治疗策略^[106]。

APOBEC1可编辑小肠上皮细胞中的载脂蛋白B (apolipoprotein B, apoB) mRNA，在甘油三酯和胆固醇的组织吸收、运输和消耗中发挥着重要作用^[103]。此外，APOBEC1蛋白在防御逆转录病毒和逆转录元件方面也发挥着关键作用^[104-105]。APOBEC2参与骨骼肌和心肌的分化^[30]，并调节TGF-β信号传导，该信号传导决定了脊椎动物胚胎发育过程中的侧向不对称性^[107]。APOBEC2与肺肿瘤、肝癌和肝脏炎症之间存在一定的关联^[9,34]。在APOBEC3的7个同源物中，除APOBEC3E外，其表达谱和功能具有组织特异性。APOBEC3不仅具有胞嘧啶脱氨酶活性，还具有水解酶活性；在细胞色素C的电子传递过程中，APOBEC3DE和APOBEC3F发挥着重要作用；DNA的修饰过程也涉及APOBEC3A、APOBEC3B和APOBEC3C的参与，其中APOBEC3H参与了DNA去甲基化过程；APOBEC3A、APOBEC3B、APOBEC3C和APOBEC3H在基因组的不稳定与癌症等疾病过程中发挥基因突变作用；此外，APOBEC3基因编码抗病毒因子，通过诱导超突变来限制逆转录病毒、逆转录元件和许多其他病毒的复制，并参与病毒的防御应答，在机体抵御病毒感染的过程中发挥着重要的功能^[108-109]。Kim等^[38]研究发现，在新冠肺炎疫情期间，突变的SARS-CoV-2新毒株更具传染性或可能逃避疫苗作用，具有广泛抗病毒活性的宿主APOBEC胞嘧啶脱氨酶可能在其中发挥重要作用，APOBEC3A、APOBEC1和APOBEC3G可以编辑SARS-CoV-2的RNA特定位点，产生C-to-U突变，这表明SARS-CoV-2可能利用APOBEC介导的突变来适应和进化。APOBEC4是近年来发现的AID/APOBEC家族新成员，关于其分子功能和底物特异性的研究相对较少，但是近年来的一些研究也发现APOBEC4与病毒感染存在一定的关系。

此外，研究发现异常的APOBEC家族表达模式可通过增加基因组突变频率来改变肿瘤免疫微环境，从而诱导免疫耗竭表型。有研究者开发了一个基于亚型生物标志物的预测风险模型，该模型对ccRCC患者表现良好，并验证了APOBEC3B的临床影响，为指导临床治疗以及将APOBEC3B作为ccRCC的新治疗靶点提供了思路^[110]。Yang等^[111]发现恒河猴APOBEC3G对线性和发夹环DNA的编辑功能，被靶标-C编辑位点3′方向下游存在的AA或GA二核苷酸基序增强，该研究结果阐明了APOBEC3G协同功能的分子机制，对其抗病毒作用及其对癌症基因组突变的贡献至关重要。Ferré等^[112]评估了在病毒全基因组和基因水平上的遗传多样性和APOBEC3诱导的突变，发现低风险型HPV (low‐risk HPVs, lrHPVs)中比高风险型HPV (high‐risk HPVs, hrHPVs)中更常见APOBEC3诱导的突变；针对最常见的lrHPV6和lrHPV11以及hrHPV16和hrHPV18，APOBEC3诱导的突变主要在lrHPVs的E4和E6基因中发现，但在hrHPVs的这些基因中几乎不存在；可变的APOBEC3突变特征可能导致HPV之间具有不同的致癌潜力，需要进一步的研究来最终确定APOBEC3编辑水平是否与不同类型和亚系的HPV致癌潜力有关。Kawale等^[113]研究表明，癌症细胞中APOBEC3A和APOBEC3B的异常表达导致许多肿瘤类型中具有特定单碱基取代特征的突变的积累；除了促进突变外，APOBEC3A和APOBEC3B还通过其催化活性诱导DNA复制应激、DNA损伤和染色体不稳定，引发一系列细胞反应；因此，APOBEC3A/B已成为癌症发展过程中基因组进化的关键驱动因素，有助于肿瘤发生、肿瘤异质性和治疗耐药性。此外，Van Norden等^[114]还发现导致RNA中C to T变化的4.5%的非同义DNA单核苷酸多态性可能是APOBEC3A/G RNA编辑的位点；由这种多态性产生的变异蛋白也可能是瞬时RNA编辑的结果；这些多态性与10类疾病中超过20%的医学问题相关，包括营养和代谢疾病、肿瘤、心血管疾病和神经系统疾病；由于RNA编辑是短暂的，因此未来的工作对于确认这种编辑对人类的影响程度是必要的。

基金

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“十四五” 广东省农业科技创新十大主攻方向 “揭榜挂帅” 项目(2024KJ14)
广东省畜禽疫病防治研究重点实验室项目(2023B1212060040)
猪禽种业全国重点实验室项目(2023QZ-NK13)
猪禽种业全国重点实验室项目(ZQQZ-55)
猪禽种业全国重点实验室项目(2023QZ-NK05)
猪禽种业全国重点实验室项目(GDNKY-ZQQZ-K07)
广东省基础与应用基础研究基金(2021A1515011125)

参考文献

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2025年第65卷第5期

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doi: 10.13343/j.cnki.wsxb.20240673

接收时间：2024-10-31
首发时间：2026-02-05
出版时间：2025-05-04

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收稿日期：2024-10-31
录用日期：2024-12-31

基金

Open Competition Program of Top Ten Critical Priorities of Agricultural Science and Technology Innovation for the 14th Five-year Plan of Guangdong Province(2024KJ14)

“十四五” 广东省农业科技创新十大主攻方向 “揭榜挂帅” 项目(2024KJ14)

Special Fund for Key Laboratory of Livestock Disease Prevention of Guangdong Province(2023B1212060040)

广东省畜禽疫病防治研究重点实验室项目(2023B1212060040)

State Key Laboratory of Swine and Poultry Breeding Industry Project(2023QZ-NK13)

猪禽种业全国重点实验室项目(2023QZ-NK13)

State Key Laboratory of Swine and Poultry Breeding Industry Project(ZQQZ-55)

猪禽种业全国重点实验室项目(ZQQZ-55)

State Key Laboratory of Swine and Poultry Breeding Industry Project(2023QZ-NK05)

猪禽种业全国重点实验室项目(2023QZ-NK05)

猪禽种业全国重点实验室项目(GDNKY-ZQQZ-K07)

Guangdong Basic and Applied Basic Research Foundation(2021A1515011125)

广东省基础与应用基础研究基金(2021A1515011125)

作者信息

^1.广东省农业科学院动物卫生研究所，广东省畜禽疫病防治研究重点实验室，广东广州

^2.西北农林科技大学动物医学院，陕西杨凌

^3.华南农业大学兽医学院，广东广州

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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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名称 Name	功能 Function	文献 References
AID	AID relies on loop7 in its structure, which is far away from the active center, to recognize the immunoglobulin single chain gene fragment 5′-WC-3′ (W=A/T, R=A/G) and exert C-to-U gene editing function	[14]
Editing the genome of viruses (such as hepatitis B virus) or deaminase independent mechanisms to inhibit virus replication	[15]
APOBEC1	APOBEC1 has a conserved zinc finger domain and deamination active site, and its N-terminus contains a nuclear localization signal that plays an important role in editing reactions and may participate in the binding of accessory proteins	[16]
Single mutants of L180, L182, I185, and L189, as well as double mutants of P190A/P191A, can all cause partial or almost complete loss of editing activity of APOBEC1	[17]
Specific editing of cytosine in ApoB 100 pre mRNA yields truncated ApoB48, ApoB 100 can transport endogenous cholesterol and triglycerides in the blood. ApoB48 plays a role in metabolizing dietary lipids	[18-19]
RBM46 can promote APOBEC1 to do the C-to-U editing of ApoB mRNA	[20]
Inducing DNA mutations or other mechanisms to inhibit certain viruses and reverse transcriptase elements	[21-22]
Promote polarization of M1 macrophages	[23-24]
Affects cancer genes or other pathological processes, such as, affects central nervous system lesions, APOBEC1 catalyzed C-to-U editing also exists in neurofibromas and lung adenocarcinoma	[25-27]
APOBEC2	Regulating and maintaining muscle development in mammals, leading to changes in muscle fiber subtypes, weight loss, and myopathy	[28-29]
Related to lung tumors, liver inflammation, and liver cancer	[30]
APOBEC3A	Specific deamination effect	[31]
Synergistic dimerization regulates the binding specificity of ssDNA	[32-33]
Responding to interferon-α in macrophages and monocytes, inhibiting viruses such as HIV-1, HPV, AAV, RSV, HTLV-1, etc.	[34-36]
During the polarization process of M1 macrophages, APOBEC3A mediates specific C to U RNA editing, thereby altering the amino acid sequences of proteins related to the pathogenesis of viral diseases and other large quantities of proteins	[37-38]
APOBEC3A exerts deamination ability by recognizing 5-methylcytosine (5mC), which is related to the clearance of viruses carrying CpG methylation	[39]
Editing the DNA of HeLa cells and U937 cells with Nox enzyme leads to ROS production, inducing the formation of pro-inflammatory state, which may be related to tumorigenesis	[40]
APOBEC3B	Effectively inhibit HIV-2 by relying on Vif	[41]
Human A3B has catalytic activity and inhibits HIV-1, while rhesus monkey A3B has no ability to inhibit HIV-1	[42]
DExD/H-box helicase 9 inhibits the binding of A3B to pgRNA and antagonizes the inhibitory effect of A3B on HBV	[43]
May be an important factor in inducing cancer mutations	[44-46]
Related to cell cycle deviation, cell death, DNA breakage, accumulation of γ-H2AX, and C to T transition	[47]
APOBEC3C	The antiviral function of A3CS188 dimer is significant	[48-49]
The inhibitory effect on HIV-1 is weak, but the anti-SIV function is strong. Simultaneously possessing the ability to inhibit viruses such as HSV-1, EBV, HBV, etc.	[50-53]
APOBEC3DE	Inhibition of HIV-1 and SIV virus replication	[54]
APOBEC3F	Inhibition of PERV and PRRSV replication	[55-56]
CAEV’s Vif induces degradation of sheep A3F and antagonizes the inhibitory effect of A3F on the virus	[57]
The driving factors of mutations in human monkeypox virus	[58]
A3F expression in cancer triple negative breast cancer is associated with tumor microenvironment invasion, activation of cancer immunity, and improved survival rate	[59]
APOBEC4	Participate in mouse spermatogenesis	[60]
Enhance HIV-1 production in a dose-dependent manner and have an effect on viral LTRs	[61]
Chicken APOBEC4 can inhibit the replication of NDV, IBDV, and H9	[62]

名称

Name

功能

Function

文献

References

AID

AID relies on loop7 in its structure, which is far away from the active center, to recognize the immunoglobulin single chain gene fragment 5′-WC-3′ (W=A/T, R=A/G) and exert C-to-U gene editing function

[14]

Editing the genome of viruses (such as hepatitis B virus) or deaminase independent mechanisms to inhibit virus replication

[15]

APOBEC1

APOBEC1 has a conserved zinc finger domain and deamination active site, and its N-terminus contains a nuclear localization signal that plays an important role in editing reactions and may participate in the binding of accessory proteins

[16]

Single mutants of L180, L182, I185, and L189, as well as double mutants of P190A/P191A, can all cause partial or almost complete loss of editing activity of APOBEC1

[17]

Specific editing of cytosine in ApoB 100 pre mRNA yields truncated ApoB48, ApoB 100 can transport endogenous cholesterol and triglycerides in the blood. ApoB48 plays a role in metabolizing dietary lipids

[18-19]

RBM46 can promote APOBEC1 to do the C-to-U editing of ApoB mRNA

[20]

Inducing DNA mutations or other mechanisms to inhibit certain viruses and reverse transcriptase elements

[21-22]

Promote polarization of M1 macrophages

[23-24]

Affects cancer genes or other pathological processes, such as, affects central nervous system lesions, APOBEC1 catalyzed C-to-U editing also exists in neurofibromas and lung adenocarcinoma

[25-27]

APOBEC2

Regulating and maintaining muscle development in mammals, leading to changes in muscle fiber subtypes, weight loss, and myopathy

[28-29]

Related to lung tumors, liver inflammation, and liver cancer

[30]

APOBEC3A

Specific deamination effect

[31]

Synergistic dimerization regulates the binding specificity of ssDNA

[32-33]

Responding to interferon-α in macrophages and monocytes, inhibiting viruses such as HIV-1, HPV, AAV, RSV, HTLV-1, etc.

[34-36]

During the polarization process of M1 macrophages, APOBEC3A mediates specific C to U RNA editing, thereby altering the amino acid sequences of proteins related to the pathogenesis of viral diseases and other large quantities of proteins

[37-38]

APOBEC3A exerts deamination ability by recognizing 5-methylcytosine (5mC), which is related to the clearance of viruses carrying CpG methylation

[39]

Editing the DNA of HeLa cells and U937 cells with Nox enzyme leads to ROS production, inducing the formation of pro-inflammatory state, which may be related to tumorigenesis

[40]

APOBEC3B

Effectively inhibit HIV-2 by relying on Vif

[41]

Human A3B has catalytic activity and inhibits HIV-1, while rhesus monkey A3B has no ability to inhibit HIV-1

[42]

DExD/H-box helicase 9 inhibits the binding of A3B to pgRNA and antagonizes the inhibitory effect of A3B on HBV

[43]

May be an important factor in inducing cancer mutations

[44-46]

Related to cell cycle deviation, cell death, DNA breakage, accumulation of γ-H2AX, and C to T transition

[47]

APOBEC3C

The antiviral function of A3CS188 dimer is significant

[48-49]

The inhibitory effect on HIV-1 is weak, but the anti-SIV function is strong. Simultaneously possessing the ability to inhibit viruses such as HSV-1, EBV, HBV, etc.

[50-53]

APOBEC3DE

Inhibition of HIV-1 and SIV virus replication

[54]

APOBEC3F

Inhibition of PERV and PRRSV replication

[55-56]

CAEV’s Vif induces degradation of sheep A3F and antagonizes the inhibitory effect of A3F on the virus

[57]

The driving factors of mutations in human monkeypox virus

[58]

A3F expression in cancer triple negative breast cancer is associated with tumor microenvironment invasion, activation of cancer immunity, and improved survival rate

[59]

APOBEC4

Participate in mouse spermatogenesis

[60]

Enhance HIV-1 production in a dose-dependent manner and have an effect on viral LTRs

[61]

Chicken APOBEC4 can inhibit the replication of NDV, IBDV, and H9

[62]