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.

中文翻译：

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分泌性自噬在溶酶体抑制后维持蛋白质稳态

内溶酶体系统在自噬降解和分泌途径中发挥着核心作用，包括细胞外囊泡和颗粒（EVP）的释放。尽管之前的工作揭示了自噬和 EVP 介导的分泌之间的重要相互联系，但我们对内溶酶体抑制过程中这些分泌事件的理解仍然不完整。在这里，我们描绘了一条响应内溶酶体抑制而上调的分泌性自噬途径，该途径介导 EVP 相关的自噬货物受体（包括 p62/SQSTM1）的释放。这种分泌受到高度调节，并依赖于自噬体形成所需的多种 ATG 以及小型 GTP 酶 Rab27a。此外，通过自噬体与自溶酶体融合的基因抑制或 SARS-CoV-2 ORF3a 的表达来破坏自噬体成熟，足以诱导自噬货物受体的 EVP 分泌。最后，当经典自噬降解受损时，ATG 依赖性 EVP 分泌缓冲液可防止自噬货物受体的细胞内积累。因此，我们建议通过 EVP 进行分泌性自噬作为一种替代途径，在内溶酶体功能障碍或自噬体成熟受损期间清除隔离物质并维持蛋白质稳态。