自噬
细胞生物学
生物
蛋白质稳态
自噬体
分泌物
溶酶体
分泌途径
自噬相关蛋白13
信号转导
生物化学
内质网
高尔基体
细胞凋亡
丝裂原活化蛋白激酶激酶
酶
蛋白激酶C
作者
Tina Solvik,Tracy Nguyen,Yu-Hsiu T. Lin,Timothy Marsh,Eric J. Huang,Arun P. Wiita,Jayanta Debnath,Andrew M. Leidal
标识
DOI:10.1083/jcb.202110151
摘要
The endolysosome system plays central roles in both autophagic degradation and secretory pathways, including the release of extracellular vesicles and particles (EVPs). Although previous work reveals important interconnections between autophagy and EVP-mediated secretion, our understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition, which mediates EVP-associated release of autophagic cargo receptors, including p62/SQSTM1. This secretion is highly regulated and dependent on multiple ATGs required for autophagosome formation, as well as the small GTPase Rab27a. Furthermore, disrupting autophagosome maturation, either via genetic inhibition of autophagosome-to-autolysosome fusion or expression of SARS-CoV-2 ORF3a, is sufficient to induce EVP secretion of autophagy cargo receptors. Finally, ATG-dependent EVP secretion buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Thus, we propose secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis during endolysosomal dysfunction or impaired autophagosome maturation.
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