Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy.
Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy.
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DOI：
10.1016/j.celrep.2022.110797
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发表时间：
2022-05-10
期刊：
影响因子：
8.8
通讯作者：
Mandell, Michael A.
中科院分区：
文献类型：
--
作者：
Saha, Bhaskar;Salemi, Michelle;Williams, Geneva L.;Oh, Seeun;Paffett, Michael L.;Phinney, Brett;Mandell, Michael A.
TRIM5 α蛋白在抗逆转录病毒防御中具有多种作用，但TRIM5 α作用的机制尚不清楚。在这里，我们采用基于APEX2的蛋白质组学来鉴定TRIM5 α相互作用的伴侣。我们的蛋白质组学结果将TRIM5与其他具有抗病毒防御作用的蛋白质联系起来。此外，他们将TRIM5与线粒体自噬联系起来，线粒体自噬是一种基于自噬的线粒体质量控制模式，在几种人类疾病中受到损害。我们发现，TRIM5是帕金森依赖性和非依赖性线粒体自噬途径所必需的，其中TRIM5招募上游自噬调节剂到受损的线粒体。缺乏泛素连接酶活性的TRIM5突变体的表达不能拯救TRIM5敲除细胞中的线粒体自噬。缺乏TRIM5的细胞在基础条件下显示线粒体功能降低，并且比野生型细胞更容易响应线粒体损伤而发生免疫激活和死亡。总之，我们的研究确定了一种蛋白质的稳态作用，这种蛋白质以前只被认为具有抗病毒作用。TRIM5 α蛋白因其在抗逆转录病毒防御中的作用而闻名。Saha等人表明TRIM5 α也具有关键的稳态功能。他们报告说，TRIM5 α通过使受损线粒体（线粒体自噬）的自噬依赖性去除有助于维持线粒体质量控制。
The protein TRIM5α has multiple roles in antiretroviral defense, but the mechanisms underlying TRIM5α action are unclear. Here, we employ APEX2-based proteomics to identify TRIM5α-interacting partners. Our proteomics results connect TRIM5 to other proteins with actions in antiviral defense. Additionally, they link TRIM5 to mitophagy, an autophagy-based mode of mitochondrial quality control that is compromised in several human diseases. We find that TRIM5 is required for Parkin-dependent and -independent mitophagy pathways where TRIM5 recruits upstream autophagy regulators to damaged mitochondria. Expression of a TRIM5 mutant lacking ubiquitin ligase activity is unable to rescue mitophagy in TRIM5 knockout cells. Cells lacking TRIM5 show reduced mitochondrial function under basal conditions and are more susceptible to immune activation and death in response to mitochondrial damage than are wild-type cells. Taken together, our studies identify a homeostatic role for a protein previously recognized exclusively for its antiviral actions. The protein TRIM5α is well known for its roles in antiretroviral defense. Saha et al. show that TRIM5α also has key homeostatic functions. They report that TRIM5α helps to maintain mitochondrial quality control by enabling the autophagy-dependent removal of damaged mitochondria (mitophagy).
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