APOBEC家族蛋白的结构功能及其在疾病控制中的作用

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

摘要:

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。

Abstract:

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.