Binding of RNA by APOBEC3G controls deamination-independent restriction of retroviruses.
Binding of RNA by APOBEC3G controls deamination-independent restriction of retroviruses.
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APOBEC3G对RNA的结合控制逆转录病毒的脱氨基依赖性限制。
DOI：
10.1093/nar/gkt527
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发表时间：
2013-08
影响因子：
14.9
通讯作者：
Langlois MA
中科院分区：
文献类型：
--
作者：
Bélanger K;Savoie M;Rosales Gerpe MC;Couture JF;Langlois MA
APOBEC3G (A3G) 是一种宿主编码蛋白，可有效限制多种逆转录病毒的感染性。这可以通过依赖于催化活性的机制发生，导致新生病毒cDNA的诱变脱氨基，和/或通过独立于其催化活性的其他方式发生。目前尚不清楚独立于脱氨的过程在多大程度上对总体限制有贡献，它们到底如何工作或如何受到监管。在这里，我们表明，A3G 非催化 N 末端结构域中色氨酸 94 (W94A) 或 127 (W127A) 的丙氨酸取代严重阻碍 RNA 结合并减轻脱氨依赖性限制，同时仍保持 DNA 突变子活性。两种色氨酸 (W94A/W127A) 的取代会产生更严重的表型，其中 RNA 结合和 RNA 依赖性蛋白质寡聚化被完全消除。我们进一步证明，RNA 结合是破坏晚期逆转录物积累、防止前病毒 DNA 整合、从而限制病毒颗粒释放所特别需要的。我们没有发现脱氨酶活性对任何这些过程的限制做出重大贡献。总之，这项工作揭示了 A3G 结合 RNA 的能力与其以不依赖脱氨基的方式抑制逆转录病毒感染的能力之间存在直接相关性。
APOBEC3G (A3G) is a host-encoded protein that potently restricts the infectivity of a broad range of retroviruses. This can occur by mechanisms dependent on catalytic activity, resulting in the mutagenic deamination of nascent viral cDNA, and/or by other means that are independent of its catalytic activity. It is not yet known to what extent deamination-independent processes contribute to the overall restriction, how they exactly work or how they are regulated. Here, we show that alanine substitution of either tryptophan 94 (W94A) or 127 (W127A) in the non-catalytic N-terminal domain of A3G severely impedes RNA binding and alleviates deamination-independent restriction while still maintaining DNA mutator activity. Substitution of both tryptophans (W94A/W127A) produces a more severe phenotype in which RNA binding and RNA-dependent protein oligomerization are completely abrogated. We further demonstrate that RNA binding is specifically required for crippling late reverse transcript accumulation, preventing proviral DNA integration and, consequently, restricting viral particle release. We did not find that deaminase activity made a significant contribution to the restriction of any of these processes. In summary, this work reveals that there is a direct correlation between A3G’s capacity to bind RNA and its ability to inhibit retroviral infectivity in a deamination-independent manner.
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