Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection
Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection
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DOI：
10.1091/mbc.e08-11-1092
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发表时间：
2009-06-01
影响因子：
3.3
通讯作者：
Nagata, Kazuhiro
中科院分区：
文献类型：
--
作者：
Ishida, Yoshihito;Yamamoto, Akitsugu;Nagata, Kazuhiro
I型胶原蛋白是细胞外基质的主要成分，胶原蛋白基因突变可引起多种基质相关疾病。这些突变的前胶原错误折叠，经常聚集在内质网（ER）中。虽然错误折叠的前胶原对细胞有潜在的毒性，但人们对它们是如何从内质网中清除的知之甚少。在这里，我们发现最初可以三聚体化但随后聚集在内质网中的前胶原通过自噬-溶酶体途径被消除，而不是通过内质网相关降解（ERAD）途径。通过特异性抑制剂抑制自噬或rnai介导的自噬相关基因的敲低可显著刺激内质网中聚集的前胶原三聚体的积累，并用雷帕霉素激活自噬可减少聚集物的数量。相反，具有形成三聚体能力受损的突变前胶原被ERAD降解。此外，我们发现自噬在保护细胞免受无效率的前胶原聚集体的毒性方面起着至关重要的作用。聚集的前胶原蛋白的自噬消除独立于ERAD系统发生。这些结果表明，自噬是针对ERAD无法清除的er积累的细胞毒性聚集体的最终细胞保护策略。
Type I collagen is a major component of the extracellular matrix, and mutations in the collagen gene cause several matrix-associated diseases. These mutant procollagens are misfolded and often aggregated in the endoplasmic reticulum (ER). Although the misfolded procollagens are potentially toxic to the cell, little is known about how they are eliminated from the ER. Here, we show that procollagen that can initially trimerize but then aggregates in the ER are eliminated by an autophagy-lysosome pathway, but not by the ER-associated degradation (ERAD) pathway. Inhibition of autophagy by specific inhibitors or RNAi-mediated knockdown of an autophagy-related gene significantly stimulated accumulation of aggregated procollagen trimers in the ER, and activation of autophagy with rapamycin resulted in reduced amount of aggregates. In contrast, a mutant procollagen which has a compromised ability to form trimers was degraded by ERAD. Moreover, we found that autophagy plays an essential role in protecting cells against the toxicity of the ERAD-inefficient procollagen aggregates. The autophagic elimination of aggregated procollagen occurs independently of the ERAD system. These results indicate that autophagy is a final cell protection strategy deployed against ER-accumulated cytotoxic aggregates that are not able to be removed by ERAD.