Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States.
Front Immunol. 2021 May 6;12:682624. doi: 10.3389/fimmu.2021.682624. eCollection 2021.
Ubiquitination is a process that acts upon every step of the HIV replication cycle. The activity, subcellular localization, and stability of HIV dependency factors as well as negative modulators can be affected by ubiquitination. These modifications consequently have an impact on the progression and outcome of infection. Additionally, recent findings suggest new roles for ubiquitination in the interplay between HIV and the cellular environment, specifically in the interactions between HIV, autophagy and apoptosis. On one hand, autophagy is a defense mechanism against HIV that promotes the degradation of the viral protein Gag, likely through ubiquitination. Gag is an essential structural protein that drives virion assembly and release. Interestingly, the ubiquitination of Gag is vital for HIV replication. Hence, this post-translational modification in Gag represents a double-edged sword: necessary for virion biogenesis, but potentially detrimental under conditions of autophagy activation. On the other hand, HIV uses Nef to circumvent autophagy-mediated restriction by promoting the ubiquitination of the autophagy inhibitor BCL2 through Parkin/PRKN. Although the Nef-promoted ubiquitination of BCL2 occurs in both the endoplasmic reticulum (ER) and mitochondria, only ER-associated ubiquitinated BCL2 arrests the progression of autophagy. Importantly, both mitochondrial BCL2 and PRKN are tightly connected to mitochondrial function and apoptosis. Hence, by enhancing the PRKN-mediated ubiquitination of BCL2 at the mitochondria, HIV might promote apoptosis. Moreover, this effect of Nef might account for HIV-associated disorders. In this article, we outline our current knowledge and provide perspectives of how ubiquitination impacts the molecular interactions between HIV, autophagy and apoptosis.
泛素化是一个作用于 HIV 复制周期各个步骤的过程。HIV 依赖因子的活性、亚细胞定位和稳定性以及负调节剂都可能受到泛素化的影响。这些修饰继而会对感染的进展和结果产生影响。此外，最近的研究结果表明，泛素化在 HIV 与细胞环境的相互作用中具有新的作用，特别是在 HIV、自噬和凋亡之间的相互作用中。一方面，自噬是一种针对 HIV 的防御机制，它通过促进病毒蛋白 Gag 的降解来促进病毒的复制，可能是通过泛素化。Gag 是一种重要的结构蛋白，它驱动病毒粒子的组装和释放。有趣的是，Gag 的泛素化对于 HIV 的复制至关重要。因此，这种 Gag 的翻译后修饰是一把双刃剑：对于病毒粒子的生物发生是必要的，但在自噬激活的情况下可能是有害的。另一方面，HIV 通过利用 Nef 促进自噬抑制剂 BCL2 的泛素化，从而避开自噬介导的限制，这种泛素化是通过 Parkin/PRKN 来实现的。虽然 Nef 促进的 BCL2 泛素化发生在内质网 (ER) 和线粒体中，但只有 ER 相关的泛素化 BCL2 才能阻止自噬的进展。重要的是，线粒体中的 BCL2 和 PRKN 都与线粒体功能和凋亡紧密相连。因此，通过增强线粒体中 PRKN 介导的 BCL2 泛素化，HIV 可能会促进凋亡。此外，Nef 的这种作用可能是导致 HIV 相关疾病的原因。在本文中，我们概述了我们目前对泛素化如何影响 HIV、自噬和凋亡之间分子相互作用的认识，并提供了一些观点。
