Many enveloped viruses bud from the plasma membrane that is tightly associated with a dense and thick actin cortex. This actin network represents a significant challenge for membrane deformation and scission, and how it is remodeled during the late steps of the viral cycle is largely unknown. Using superresolution microscopy, we show that HIV-1 buds in areas of the plasma membrane with low cortical F-actin levels. We find that the cellular oxidoreductase MICAL1 locally depolymerizes actin at budding sites to promote HIV-1 budding and release. Upon MICAL1 depletion, F-actin abnormally remains at viral budding sites, incompletely budded viruses accumulate at the plasma membrane and viral release is impaired. Remarkably, normal viral release can be restored in MICAL1-depleted cells by inhibiting Arp2/3-dependent branched actin networks. Mechanistically, we find that MICAL1 directly disassembles branched-actin networks and controls the timely recruitment of the Endosomal Sorting Complexes Required for Transport scission machinery during viral budding. In addition, the MICAL1 activator Rab35 is recruited at budding sites, functions in the same pathway as MICAL1, and is also required for viral release. This work reveals a role for oxidoreduction in triggering local actin depolymerization to control HIV-1 budding, a mechanism that may be widely used by other viruses. The debranching activity of MICAL1 could be involved beyond viral budding in various other cellular functions requiring local plasma membrane deformation.

中文翻译：

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HIV-1 出芽需要氧化还原酶 MICAL1 分解皮质肌动蛋白


许多包膜病毒从质膜中萌芽，质膜与致密而厚的肌动蛋白皮层紧密相关。这种肌动蛋白网络对膜变形和断裂构成了重大挑战，并且在病毒周期的后期如何重塑在很大程度上是未知的。使用超分辨率显微镜，我们显示 HIV-1 芽位于皮质膜 F-肌动蛋白水平低的区域。我们发现细胞氧化还原酶 MICAL1 在出芽位点局部解聚肌动蛋白，以促进 HIV-1 出芽和释放。在 MICAL1 耗竭后，F-肌动蛋白异常保留在病毒出芽位点，未完全出芽的病毒在质膜上积累，病毒释放受损。值得注意的是，通过抑制 Arp2/3 依赖性分支肌动蛋白网络，可以在 MICAL1 耗尽的细胞中恢复正常的病毒释放。从机制上讲，我们发现 MICAL1 直接分解支链肌动蛋白网络并控制病毒出芽期间运输剪刀机制所需的内体分选复合物的及时募集。此外，MICAL1 激活剂 Rab35 在出芽位点募集，与 MICAL1 在同一通路发挥作用，也是病毒释放所必需的。这项工作揭示了氧化还原在触发局部肌动蛋白解聚以控制 HIV-1 出芽中的作用，这种机制可能被其他病毒广泛使用。MICAL1 的去分支活性可能涉及病毒出芽以外的各种需要局部质膜变形的其他细胞功能。