Journal article

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

Yoshihito Ishida, Akitsugu Yamamoto, Akira Kitamura, Shireen R Lamande, Tamotsu Yoshimori, John F Bateman, Hiroshi Kubota, Kazuhiro Nagata



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 accumul..

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Awarded by Creative Scientific Research

Awarded by Grants-in-Aid for Scientific Research

Funding Acknowledgements

We thank Dr. Rainer Pepperkok (European Molecular Biology Laboratory, Germany) for providing the GFP-pro alpha 1(I) expression vector, Dr. Larry W. Fisher (National Institutes of Health, MD) for the antibody to the type I procollagen alpha 1 chain C-propeptide (LF-41) and Dr. Nobuko Hosokawa (Kyoto University, Japan) for the alpha 1-antitrypsin NHK variant expression vector. We are grateful to Dr. Motoko Naitoh (Kyoto University, Japan) and Dr. Naonobu Fujita (Osaka University, Japan) for technical comments and suggestions. Y. I. and A. K. were supported by fellowships from the Japan Society for the Promotion of Science. K. N. was supported by a Grant-in-Aid for Creative Scientific Research (19GS0314). K. N. and H. K. were supported by a Ground-based Research Program for Space Utilization from the Japan Space Forum. J. B. and S. L. are supported by grants from the National Health and Medical Research Council of Australia.