Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in initiation of lysophagy
Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in initiation of lysophagy
复制标题
DOI：
10.1016/j.celrep.2022.111349
复制
发表时间：
2022-09-13
期刊：
影响因子：
8.8
通讯作者：
Hamasaki, Maho
中科院分区：
文献类型：
--
作者：
Teranishi, Hirofumi;Tabata, Keisuke;Hamasaki, Maho
巨噬是一种整体降解系统，其中称为自噬体的双膜结合结构将细胞质物质传递给溶酶体。自噬通过选择性地识别和隔离特定靶标（如受损的细胞器、蛋白质聚集体和入侵细菌）来促进细胞稳态，称为选择性自噬。我们之前报道了一种选择性自噬，即溶噬，它有助于清除受损的溶酶体。受损的溶酶体泛素化并招募自噬机制。使用转染试剂包被球的蛋白质组学研究和进一步的评估表明，CUL4A-DDB1-WDFY1 E3泛素连接酶复合物对于启动溶噬和清除受损的溶酶体至关重要。此外，我们发现LAMP2作为受损溶酶体的底物被CUL4A E3连接酶复合物泛素化。这些结果揭示了细胞如何选择性地标记受损的溶酶体以启动自噬以清除溶酶体。
Macroautophagy is a bulk degradation system in which double membrane-bound structures called autophago-somes to deliver cytosolic materials to lysosomes. Autophagy promotes cellular homeostasis by selectively recognizing and sequestering specific targets, such as damaged organelles, protein aggregates, and invading bacteria, termed selective autophagy. We previously reported a type of selective autophagy, lysophagy, which helps clear damaged lysosomes. Damaged lysosomes become ubiquitinated and recruit autophagic machin-ery. Proteomic studies using transfection reagent-coated beads and further evaluations reveal that a CUL4A-DDB1-WDFY1 E3 ubiquitin ligase complex is essential to initiate lysophagy and clear damaged lysosomes. Moreover, we show that LAMP2 is ubiquitinated by the CUL4A E3 ligase complex as a substrate on damaged lysosomes. These results reveal how cells selectively tag damaged lysosomes to initiate autophagy for the clearance of lysosomes.