人类胞嘧啶脱氨酶APOBEC3F(A3F)及APOBEC3G(A3G)抑制了人类免疫缺陷病毒1型(HIV-1)的复制。当缺乏HIV-1 Vif(Vif对HIV并非必不可少,但可能影响游离HIV感染性、病毒体的产生和体内传播)时,A3F/A3G合并组装病毒颗粒,并在随后被感染的靶细胞发挥抗病毒功能。
A3F及A3G合并成病毒颗粒,随后在蛋白酶成熟的病毒颗粒核心内的形成衣壳化,这些作用有可能对这些蛋白的抗病毒功能是重要的。在这篇文章中,美国范德堡大学医学院John P. Donahue等人阐明了在成熟的病毒颗粒核心A3F被定量衣壳化的机制。相关论文发表在3月28日的The Journal of Biological Chemistry。
与A3F显著的不同,A3G分布在病毒颗粒核心内及核心外。通过分析一系列包含N端及C端脱氨基酶的A3F-A3G嵌合体,鉴定了一个位于A3F的C末端脱氨酶结构域的14个氨基酸片段,发现它可以促进优先的衣壳化及抗HIV活性。位于这个C端区域的氨基酸残基L306被发现对这些功能是必需的但不是充分的。在N端脱氨酶结构域的氨基酸残基W126被发现也促进了优先的衣壳化以及A3F的抗病毒活性。对A3F(W126A L306A)双重突变株的分析表明,这两种残基对完整的抗HIV功能是必需的。
这项研究增进了对A3F病毒颗粒衣壳化及抗病毒功能的机制的了解,也将会促进抑制HIV-1复制新策略的研究。(生物谷Deepblue编译)
doi: 10.1074/jbc.M111.310839
PMC:
PMID:
Signals in APOBEC3F N-terminal and C-terminal Deaminase Domains Each Contribute to Encapsidation in HIV-1 Virions and Are Both Required for HIV-1 Restriction
Chisu Song, Lorraine Sutton, Megan E. Johnson, Richard T. D'Aquila and John P. Donahue.
Human cytidine deaminases APOBEC3F (A3F) and APOBEC3G (A3G) inhibit human immunodeficiency virus type-1 (HIV-1) replication.In the absence of HIV-1 Vif, A3F and/or A3G are incorporated into assembling virions and exert antiviral functions in subsequently infected target cells.Encapsidation of A3F or A3G within the protease-matured virion core following their incorporation into virions is hypothesized to be important for the antiviral function of these proteins. In this report, we demonstrated that A3F was quantitatively encapsidated in the mature virion core.In distinct contrast, A3G was distributed both within and outside of the virion core. Analysis of a series of A3F-A3G chimeras comprised of exchanged N- and C-terminal deaminase domains identified a 14 amino acid segment in the A3F C-terminal deaminase domain that contributed to preferential encapsidation and anti-HIV activity.Amino acid residue L306 in this C-terminal segment was determined to be necessary, but not sufficient, for these effects. Amino acid residue W126 in the N-terminal deaminase domain was determined also to contribute to preferential encapsidation and antiviral activity of A3F.Analysis of the A3F (W126A L306A) double mutant revealed that both residues are required for full anti-HIV function.The results reported here advance our understanding of the mechanisms of A3F virion encapsidation and antiviral function and may lead to innovative strategies to inhibit HIV-1 replication.