TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
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DOI：
10.1016/j.molcel.2023.02.023
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发表时间：
2023-03
期刊：
影响因子：
16
通讯作者：
François Le Guerroué;Eric N Bunker;William M. Rosencrans;J. Nguyen;Mohammed A. Basar;Achim Werner;
中科院分区：
文献类型：
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作者：
François Le Guerroué;Eric N Bunker;William M. Rosencrans;J. Nguyen;Mohammed A. Basar;Achim Werner;
线粒体自噬是选择性自噬的一种形式，它以严格控制的方式处理多余的和可能引起损伤的细胞器。虽然参与线粒体自噬诱导的机制是众所周知的，但其组成部分的调节尚不清楚。在这里，我们证明 HeLa 细胞中 TNIP1 敲除会加速线粒体自噬速率，而异位 TNIP1 会负向调节线粒体自噬速率。 TNIP1 的这些功能取决于进化上保守的 LIR 基序以及 AHD3 结构域，它们分别是与 LC3/GABARAP 蛋白家族和自噬受体 TAX1BP1 结合所必需的。我们进一步表明，磷酸化似乎调节其与 ULK1 复合体成员 FIP200 的关联，使 TNIP1 能够与自噬受体竞争，这为其在线粒体自噬过程中的抑制功能提供了分子原理。综上所述，我们的研究结果将 TNIP1 描述为线粒体自噬的负调节因子，在自噬体生物发生的早期步骤发挥作用。
Mitophagy is a form of selective autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in mitophagy induction is well known, the regulation of the components is less clear. Here, we demonstrate that TNIP1 knockout in HeLa cells accelerates mitophagy rates and that ectopic TNIP1 negatively regulates the rate of mitophagy. These functions of TNIP1 depend on an evolutionarily conserved LIR motif as well as an AHD3 domain, which are required for binding to the LC3/GABARAP family of proteins and the autophagy receptor TAX1BP1, respectively. We further show that phosphorylation appears to regulate its association with the ULK1 complex member FIP200, allowing TNIP1 to compete with autophagy receptors, which provides a molecular rationale for its inhibitory function during mitophagy. Taken together, our findings describe TNIP1 as a negative regulator of mitophagy that acts at the early steps of autophagosome biogenesis.