Mikhail Sheridan, Soleimanpour Scott A
Departments of Internal Medicine and Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Veterans Affairs Ann Arbor Health Care System, Ann Arbor, MI 48105, USA.
Autophagy Rep. 2023;2(1). doi: 10.1080/27694127.2023.2242054. Epub 2023 Aug 1.
Mitophagy is a central component of the mitochondrial quality control machinery, which is necessary for cellular viability and bioenergetics. The E3 ubiquitin ligase CLEC16A (C-type lectin domain containing 16A) forms a tripartite mitophagy regulatory complex together with the E3 ligase RNF41 (ring finger protein 41) and the ubiquitin-specific peptidase USP8 (ubiquitin specific peptidase 8), yet CLEC16A structural/functional domains relevant for mitophagy are unknown. We identify that CLEC16A contains an internal intrinsically disordered region (IDR), which is important for CLEC16A function and stability. IDRs are flexible domains lacking fixed secondary structure and regulate an emerging number of diverse processes, yet they have been largely unstudied in mitophagy. We observe that the internal CLEC16A IDR is essential for CLEC16A degradation and is bound by RNF41 to promote CLEC16A turnover. This IDR also promotes assembly of the CLEC16A-RNF41-USP8 mitophagy regulatory complex. Thus, our study revealed the importance of IDRs in mitophagy via the regulation of CLEC16A abundance by RNF41, opening new structural insights into mitochondrial quality control.
线粒体自噬是线粒体质量控制机制的核心组成部分，对细胞活力和生物能量学至关重要。E3泛素连接酶CLEC16A（含C型凝集素结构域16A）与E3连接酶RNF41（环指蛋白41）和泛素特异性肽酶USP8（泛素特异性肽酶8）形成三方线粒体自噬调节复合物，但与线粒体自噬相关的CLEC16A结构/功能结构域尚不清楚。我们发现CLEC16A包含一个内部无序区域（IDR），这对CLEC16A的功能和稳定性很重要。IDR是缺乏固定二级结构的柔性结构域，可调节大量不同的过程，但它们在很大程度上尚未在线粒体自噬中得到研究。我们观察到CLEC16A内部的IDR对CLEC16A的降解至关重要，并被RNF41结合以促进CLEC16A的周转。这个IDR还促进了CLEC16A-RNF41-USP8线粒体自噬调节复合物的组装。因此，我们的研究揭示了IDR在线粒体自噬中的重要性，即通过RNF41调节CLEC16A的丰度，为线粒体质量控制开辟了新的结构见解。
