ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion.
ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion.
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DOI：
10.1016/j.devcel.2023.03.014
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发表时间：
2023-04
影响因子：
11.8
通讯作者：
Fulong Wang;R. Peters;Jingyue Jia;M. Mudd;M. Salemi;Lee Allers;Ruheena Javed;Thabata Duque;M. Paddar;Einar S. Trosdal;B. Phinney;V. Deretic
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文献类型：
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作者：
Fulong Wang;R. Peters;Jingyue Jia;M. Mudd;M. Salemi;Lee Allers;Ruheena Javed;Thabata Duque;M. Paddar;Einar S. Trosdal;B. Phinney;V. Deretic
ATG 5是E3连接酶的一部分，指导ATG 8蛋白的脂化，这是膜atg 8化和典型自噬的核心过程。髓样细胞中Atg 5的缺失导致结核病小鼠模型的早期死亡。该蛋白的体内表型对ATG 5具有特异性。在这里，我们使用人类细胞系显示，缺乏ATG 5，但不存在其他指导典型自噬的ATG，促进溶酶体胞吐和细胞外囊泡的分泌，以及在鼠Atg 5 fl/flLysM-Cre中性粒细胞中，它们的过度脱粒。这是由于ATG 5敲除细胞中的溶酶体破损和ESCRT蛋白阿利克斯的替代缀合复合物ATG 12-ATG 3的螯合，其在膜修复和外泌体分泌中起作用。这些发现揭示了以前未描述的功能，ATG 5在其主机的保护作用，在小鼠实验模型的结核病，并强调了分支方面的atg 8化共轭级联超越典型的自噬的意义。
ATG5 is a part of the E3 ligase directing lipidation of ATG8 proteins, a process central to membrane atg8ylation and canonical autophagy. Loss of Atg5 in myeloid cells causes early mortality in murine models of tuberculosis. Thisin vivophenotype is specific to ATG5. Here, we show using human cell lines that absence of ATG5, but not of other ATGs directing canonical autophagy, promotes lysosomal exocytosis and secretion of extracellular vesicles and, in murine Atg5fl/flLysM-Cre neutrophils, their excessive degranulation. This is due to lysosomal disrepair in ATG5 knockout cells and the sequestration by an alternative conjugation complex, ATG12-ATG3, of ESCRT protein ALIX, which acts in membrane repair and exosome secretion. These findings reveal a previously undescribed function of ATG5 in its host-protective role in murine experimental models of tuberculosis and emphasize the significance of the branching aspects of the atg8ylation conjugation cascade beyond the canonical autophagy.