Division of Medical Genetics, IRCCS Casa Sollievo Della Sofferenza, Viale Cappuccini, 71013 San Giovanni Rotondo, Italy.
National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy; Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
Biochim Biophys Acta Mol Cell Res. 2018 Jun;1865(6):908-919. doi: 10.1016/j.bbamcr.2018.03.011. Epub 2018 Mar 29.
Autophagy is a catabolic process needed for maintaining cell viability and homeostasis in response to numerous stress conditions. Emerging evidence indicates that the ubiquitin system has a major role in this process. TRIMs, an E3 ligase protein family, contribute to selective autophagy acting as receptors and regulators of the autophagy proteins recognizing endogenous or exogenous targets through intermediary autophagic tags, such as ubiquitin. Here we report that TRIM50 fosters the initiation phase of starvation-induced autophagy and associates with Beclin1, a central component of autophagy initiation complex. We show that TRIM50, via the RING domain, ubiquitinates Beclin 1 in a K63-dependent manner enhancing its binding with ULK1 and autophagy activity. Finally, we found that the Lys-372 residue of TRIM50, critical for its own acetylation, is necessary for its E3 ligase activity that governs Beclin1 ubiquitination. Our study expands the roles of TRIMs in regulating selective autophagy, revealing an acetylation-ubiquitination dependent control for autophagy modulation.
自噬是一种分解代谢过程，对于维持细胞活力和内环境稳定至关重要，可响应多种应激条件。新出现的证据表明，泛素系统在这个过程中起着主要作用。TRIMs 是一种 E3 连接酶蛋白家族，作为自噬蛋白的受体和调节剂，通过中间自噬标签（如泛素）识别内源性或外源性靶标，参与选择性自噬。在这里，我们报告 TRIM50 促进饥饿诱导的自噬起始阶段，并与自噬起始复合物的核心组成部分 Beclin1 相关联。我们表明，TRIM50 通过 RING 结构域以依赖于 K63 的方式泛素化 Beclin1，增强其与 ULK1 的结合和自噬活性。最后，我们发现 TRIM50 的 Lys-372 残基对其自身乙酰化至关重要，对于其控制 Beclin1 泛素化的 E3 连接酶活性也是必需的。我们的研究扩展了 TRIMs 在调节选择性自噬中的作用，揭示了自噬调节的乙酰化-泛素化依赖控制。
