The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.
The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.
复制标题
逆转录病毒限制因子 TRIM5/TRIM5α 调节线粒体质量控制。
DOI：
10.1080/15548627.2022.2084863
复制
发表时间：
2023
期刊：
影响因子：
13.3
通讯作者：
Mandell,MichaelA
中科院分区：
文献类型：
--
作者：
Saha,Bhaskar;Mandell,MichaelA
TRIM 5蛋白正在深入研究其在抗病毒防御中的作用，但其潜在的作用机制仍然难以捉摸。在我们的研究中，我们对TRIM 5相互作用的伴侣进行了公正的鉴定，发现了参与各种细胞功能的蛋白质。我们利用这个蛋白质组学数据集来揭示TRIM 5在线粒体自噬中的作用，线粒体自噬是一种在多种人类疾病中受损的线粒体质量控制系统。线粒体损伤触发TRIM 5募集到ER-线粒体接触位点，其中TRIM 5与自噬体生物发生的标记物共定位。缺乏TRIM 5的细胞不能进行PRKN依赖性和PRKN非依赖性线粒体自噬途径。TRIM 5敲除细胞显示线粒体功能降低和响应于线粒体损伤的不受控制的免疫激活;表型与线粒体自噬中对TRIM 5的要求一致。从机制上讲，我们发现TRIM 5是将自噬起始机制募集到受损线粒体所必需的，其中TRIM 5充当促进线粒体损伤的蛋白质标记物与自噬起始机制之间相互作用的支架。
The protein TRIM5 is under intensive investigation related to its roles in antiviral defense, yet its underlying mechanisms of action remain elusive. In our study, we performed an unbiased identification of TRIM5-interacting partners and found proteins participating in a wide variety of cellular functions. We utilized this proteomics data set to uncover a role for TRIM5 in mitophagy, a mitochondrial quality control system that is impaired in multiple human diseases. Mitochondrial damage triggers the recruitment of TRIM5 to ER-mitochondria contact sites where TRIM5 colocalizes with markers of autophagosome biogenesis. Cells lacking TRIM5 are unable to carry out PRKN-dependent and PRKN-independent mitophagy pathways. TRIM5 knockout cells show reduced mitochondrial function and uncontrolled immune activation in response to mitochondrial damage; phenotypes consistent with a requirement for TRIM5 in mitophagy. Mechanistically, we found that TRIM5 is required for the recruitment of the autophagy initiation machinery to damaged mitochondria, where TRIM5 acts as a scaffold promoting interactions between protein markers of mitochondrial damage and the autophagy initiation machinery.