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首页> 外文期刊>Journal of Molecular Biology >APOBEC3 multimerization correlates with HIV-1 packaging and restriction activity in living cells
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APOBEC3 multimerization correlates with HIV-1 packaging and restriction activity in living cells

机译：APOBEC3多聚化与活细胞中的HIV-1包装和限制活性有关

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摘要

APOBEC3G belongs to a family of DNA cytosine deaminases that are involved in the restriction of a broad number of retroviruses including human immunodeficiency virus type 1 (HIV-1). Prior studies have identified two distinct mechanistic steps in Vif-deficient HIV-1 restriction: packaging into virions and deaminating viral cDNA. APOBEC3A, for example, although highly active, is not packaged and is therefore not restrictive. APOBEC3G, on the other hand, although having weaker enzymatic activity, is packaged into virions and is strongly restrictive. Although a number of studies have described the propensity for APOBEC3 oligomerization, its relevance to HIV-1 restriction remains unclear. Here, we address this problem by examining APOBEC3 oligomerization in living cells using molecular brightness analysis. We find that APOBEC3G forms high-order multimers as a function of protein concentration. In contrast, APOBEC3A, APOBEC3C and APOBEC2 are monomers at all tested concentrations. Among other members of the APOBEC3 family, we show that the multimerization propensities of APOBEC3B, APOBEC3D, APOBEC3F and APOBEC3H (haplotype II) bear more resemblance to APOBEC3G than to APOBEC3A/3C/2. Prior studies have shown that all of these multimerizing APOBEC3 proteins, but not the monomeric family members, have the capacity to package into HIV-1 particles and restrict viral infectivity. This correlation between oligomerization and restriction is further evidenced by two different APOBEC3G mutants, which are each compromised for multimerization, packaging and HIV-1 restriction. Overall, our results imply that multimerization of APOBEC3 proteins may be related to the packaging mechanism and ultimately to virus restriction.
机译：APOBEC3G属于DNA胞嘧啶脱氨酶家族，参与限制包括人类1型免疫缺陷病毒（HIV-1）在内的多种逆转录病毒。先前的研究已经确定了Vif缺乏的HIV-1限制的两个不同的机理步骤：包装入病毒粒子和使病毒cDNA脱氨基。例如，虽然APOBEC3A具有很高的活性，但并未包装，因此不受限制。另一方面，APOBEC3G虽然酶的活性较弱，但被包装到病毒粒子中并具有严格的限制性。尽管许多研究描述了APOBEC3低聚的可能性，但其与HIV-1限制的相关性仍不清楚。在这里，我们通过使用分子亮度分析检查活细胞中的APOBEC3寡聚化来解决此问题。我们发现APOBEC3G形成高阶多聚体作为蛋白质浓度的函数。相反，APOBEC3A，APOBEC3C和APOBEC2在所有测试浓度下均为单体。在APOBEC3家族的其他成员中，我们表明APOBEC3B，APOBEC3D，APOBEC3F和APOBEC3H（单元型II）的多聚倾向与APOBEC3G的相似性大于与APOBEC3A / 3C / 2的相似性。先前的研究表明，所有这些多聚APOBEC3蛋白（但不是单体家族成员）都具有包装成HIV-1颗粒并限制病毒感染性的能力。寡聚和限制之间的这种相关性由两个不同的APOBEC3G突变体进一步证明，这两个突变体在多聚化，包装和HIV-1限制方面均受到损害。总体而言，我们的结果暗示APOBEC3蛋白的多聚化可能与包装机制有关，并最终与病毒限制有关。

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