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Vol. 20, Issue 11, 2744-2754, June 1, 2009

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Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection

Yoshihito Ishida^*, Akitsugu Yamamoto, Akira Kitamura^*,, Shireen R. Lamandé, Tamotsu Yoshimori^||, John F. Bateman, Hiroshi Kubota^*,¶, and Kazuhiro Nagata^*

*Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8397, Japan; Department of Cell Biology, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia; and ^||Department of Cell Regulation, Research Institute for Microbial Diseases, Osaka University, Suita-Osaka 565-0871, Japan

Submitted November 3, 2008; Revised March 26, 2009; Accepted April 1, 2009
Monitoring Editor: Jeffrey L. Brodsky

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.

Present addresses: Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Kita-ku, Sapporo 001-0021, Japan;

^¶Department of Life Science, Faculty of Engineering and Resource Science, Akita University, 1-1 Tegata-Gakuencho, Akita 010-8502, Japan.

Address correspondence to: Kazuhiro Nagata (nagata{at}frontier.kyoto-u.ac.jp)

Abbreviations used: ATZ, 1-antitrypsin Z variant; EDEM, ER-degradation enhancing -mannosidase-like protein; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum–associated degradation; Hsp47, 47-kDa heat-shock protein; NHK, 1-antitrypsin Null Hong Kong variant; OI, osteogenesis imperfecta.

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