Zymophagy, a Novel Selective Autophagy Pathway Mediated by VMP1-USP9x-p62, Prevents Pancreatic Cell Death
Zymophagy, a Novel Selective Autophagy Pathway Mediated by VMP1-USP9x-p62, Prevents Pancreatic Cell Death
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DOI：
10.1074/jbc.m110.197301
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发表时间：
2011-03-11
影响因子：
4.8
通讯作者：
Vaccaro, Maria I.
中科院分区：
文献类型：
--
作者：
Grasso, Daniel;Ropolo, Alejandro;Vaccaro, Maria I.
自噬作为一种保护或促进细胞死亡的机制最近引起了人们的极大关注，尽管不同的自噬途径以及它们发生的细胞环境仍有待阐明。我们报告了一种新的选择性自噬作为一种保护性细胞反应的彻底的细胞和生物化学表征。这种新的选择性自噬在胰腺炎诱导的囊泡转运改变过程中在胰腺腺泡细胞中被激活，以隔离和降解潜在有害的活化酶原颗粒。我们创造了“噬酶”这个术语来指这个过程。自噬相关蛋白VMP 1、泛素蛋白酶USP 9 x和泛素结合蛋白p62介导酶噬作用。此外，VMP 1与USP 9 x相互作用，表明自噬途径与选择性自噬体形成所需的泛素识别机制之间存在密切合作。在基因工程小鼠和培养的胰腺腺泡细胞中实验性胰腺炎以及在人类中急性胰腺炎可激活吞噬酶。此外，通过控制胰腺炎诱导的细胞内酶原激活和帮助防止细胞死亡，噬酶作用具有病理生理学相关性。总之，这些数据揭示了一种由VMP 1-USP 9 x-p62途径介导的新型选择性自噬形式，作为细胞保护性反应。
Autophagy has recently elicited significant attention as a mechanism that either protects or promotes cell death, although different autophagy pathways, and the cellular context in which they occur, remain to be elucidated. We report a thorough cellular and biochemical characterization of a novel selective autophagy that works as a protective cell response. This new selective autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration to sequester and degrade potentially deleterious activated zymogen granules. We have coined the term "zymophagy" to refer to this process. The autophagy-related protein VMP1, the ubiquitin-protease USP9x, and the ubiquitin-binding protein p62 mediate zymophagy. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. Zymophagy is activated by experimental pancreatitis in genetically engineered mice and cultured pancreatic acinar cells and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. Together, these data reveal a novel selective form of autophagy mediated by the VMP1-USP9x-p62 pathway, as a cellular protective response.