Reduced APOBEC3H variant anti-viral activities are associated with altered RNA binding activities.
Reduced APOBEC3H variant anti-viral activities are associated with altered RNA binding activities.
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DOI：
10.1371/journal.pone.0038771
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yu XF
中科院分区：
文献类型：
--
作者：
Zhen A;Du J;Zhou X;Xiong Y;Yu XF
APOBEC 3 H（A3 H）是APOBEC 3蛋白家族的成员，具有不同的抗逆转录病毒和逆转录转座子活性。A3 H基因含有几个单核苷酸多态性，在人类中已检测到多达7种单倍型。虽然A3 H单倍型之间的抗病毒功能的变化尚未完全了解，但已知仅含有15 N105 R的A3 H变体对Vif缺陷型HIV-1具有有效活性。7SL RNA结合和HIV-1掺入所需的APOBEC 3G（A3 G）和APOBEC 3F（A3 F）的独特基序RLYY（F/Y）W在所有A3 H变体中也是保守的。与A3 G一样，A3 H HapII也表现出对宿主小RNA如7SL和Y RNA的高结合亲和力。关键氨基酸W115 A的突变导致表达水平降低，对7SL RNA的亲和力降低，病毒粒子包装受损和抗病毒活性降低。相比之下，A3 H HapI与宿主小RNA的结合亲和力较低，病毒体掺入效率降低，导致抗病毒活性显著降低。在A3 H HapIII和HapIV中常见的SNP ΔN15消除了它们与RNA结合的能力，并且A3 H HapIIΔ 15 N未能包装成HIV-1病毒体或表现出任何抗病毒活性。最后，我们发现A3 H变体具有不同的细胞定位模式，这与它们不同的RNA结合亲和力相关。因此，Pol-III RNA如7SL RNA结合是有效抗HIV人APOBEC 3胞苷脱氨酶的保守特征。
APOBEC3H (A3H) is a member of the APOBEC3 family of proteins with varying activities against retroviruses and retrotransposons. The A3H gene contains several single nucleotide polymorphisms and up to seven haplotypes have been detected in humans. Although variations in anti-viral function among A3H haplotypes are not fully understood, only 15N105R-containing A3H variants are known to have potent activities against Vif-deficient HIV-1. Unique motif RLYY(F/Y)W of APOBEC3G (A3G) and APOBEC3F (A3F) required for 7SL RNA binding and HIV-1 incorporation is also conserved in all A3H variants. Like A3G, A3H HapII also demonstrated high binding affinity to host small RNAs such as 7SL and Y RNAs. Mutation of a critical amino acid, W115A resulted in reduced expression level, decreased affinity for 7SL RNA, impairment of virion packaging and reduced anti-viral activity. By comparison, A3H HapI had lower binding affinities to host small RNAs and reduced efficiency of virion incorporation, resulting in significantly reduced anti-viral activity. The SNP ΔN15 commonly found in A3H HapIII and HapIV abolished their abilities to associate with RNAs, and A3H HapIIΔ15N failed to package into HIV-1 virions or exhibited any anti-viral activity. Finally, we showed that A3H variants had distinct cellular localization patterns, which correlated with their different RNA binding affinities. Thus, Pol-III RNA such as 7SL RNA binding is a conserved feature of potent anti-HIV human APOBEC3 cytidine deaminases.
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