How cells recognize and remove the perforated lysosome
How cells recognize and remove the perforated lysosome
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细胞如何识别并去除穿孔的溶酶体
DOI：
10.1080/15548627.2022.2138686
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发表时间：
2022
期刊：
影响因子：
13.3
通讯作者：
Maho Hamasaki
中科院分区：
文献类型：
--
作者：
Keisuke Tabata;Marika Saeki;Tamotsu Yoshimori;Maho Hamasaki
巨自噬（以下简称自噬）是一种高度保守的细胞内降解系统，通过降解错误折叠的蛋白质、非功能性细胞器、病原体和胞质溶胶等细胞成分来维持细胞稳态。相反，选择性自噬靶向并降解特定的物质，例如细胞器、细菌等。我们之前报道过，受损的溶酶体是自噬目标，通过一个称为溶噬的过程。然而，细胞如何通过自噬靶向受损的溶酶体尚不清楚。我们进行了蛋白质组学分析，然后进行了 siRNA 筛选，以鉴定参与靶向受损溶酶体的基因，并鉴定了一种新的 E3 连接酶复合物，其中涉及 CUL4A (cullin 4A)，作为溶食作用的调节复合物。我们还发现，在溶酶体损伤过程中，该复合物介导溶酶体蛋白 LAMP2 上 K48 连接的多聚泛素化；特别是，LAMP2 的腔侧对于将复合物招募到受损的溶酶体非常重要。因此，这种蛋白质修饰对于启动受损溶酶体的清除至关重要。
Macroautophagy (hereafter autophagy) is a highly conserved intracellular degradation system to maintain cellular homeostasis by degrading cellular components such as misfolded proteins, nonfunctional organelles, pathogens, and cytosol. Conversely, selective autophagy targets and degrades specific cargo, such as organelles, bacteria,etc. We previously reported that damaged lysosomes are autophagy targets, via a process called lysophagy. However, how cells target damaged lysosomes through autophagy is not known. We performed proteomics analysis followed by siRNA screening to identify genes involved in targeting damaged lysosomes and identified a new E3 ligase complex, involving CUL4A (cullin 4A), as a regulatory complex in lysophagy. We also found that this complex mediates K48-linked poly-ubiquitination on lysosome protein LAMP2 during lysosomal damage; particularly, the lumenal side of LAMP2 is important to recruit the complex to damaged lysosomes. This protein modification is thus critical to initiate the clearance of damaged lysosomes.