Abstract：
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.
摘要：
TRIM5α蛋白在抗逆转录病毒防御中具有多种作用，但TRIM5α作用的潜在机制尚不清楚。这里,我们使用基于APEX2的蛋白质组学来鉴定TRIM5α相互作用的配偶体。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,它们将TRIM5与线粒体自噬联系起来，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损。我们发现TRIM5是Parkin依赖性和非依赖性线粒体自噬途径所必需的，其中TRIM5向受损的线粒体募集上游自噬调节因子。缺乏泛素连接酶活性的TRIM5突变体的表达无法挽救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降低的线粒体功能，并且比野生型细胞更容易受到免疫激活和响应线粒体损伤的死亡。一起来看,我们的研究确定了一种蛋白质的稳态作用，这种蛋白质以前完全被认为是抗病毒作用。
