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

被引:166
作者
Ishida, Yoshihito [1 ]
Yamamoto, Akitsugu [2 ]
Kitamura, Akira [1 ]
Lamande, Shireen R. [3 ]
Yoshimori, Tamotsu [4 ]
Bateman, John F. [3 ]
Kubota, Hiroshi [1 ]
Nagata, Kazuhiro [1 ]
机构
[1] Kyoto Univ, Inst Frontier Med Sci, Dept Mol & Cellular Biol, Sakyo Ku, Kyoto 6068397, Japan
[2] Nagahama Inst Biosci & Technol, Dept Cell Biol, Shiga 5260829, Japan
[3] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia
[4] Osaka Univ, Microbial Dis Res Inst, Dept Cell Regulat, Suita, Osaka 5650871, Japan
基金
英国医学研究理事会; 日本学术振兴会;
关键词
PROTEIN-QUALITY CONTROL; EARLY SECRETORY PATHWAY; EMBRYONIC STEM-CELLS; I COLLAGEN; OSTEOGENESIS-IMPERFECTA; MULTIVESICULAR BODIES; MOLECULAR CHAPERONE; LETHAL MUTATION; DEGRADATION; MICE;
D O I
10.1091/mbc.E08-11-1092
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2744 / 2754
页数:11
相关论文
共 52 条
[21]   Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes [J].
Klionsky, Daniel J. ;
Abeliovich, Hagai ;
Agostinis, Patrizia ;
Agrawal, Devendra K. ;
Aliev, Giumrakch ;
Askew, David S. ;
Baba, Misuzu ;
Baehrecke, Eric H. ;
Bahr, Ben A. ;
Ballabio, Andrea ;
Bamber, Bruce A. ;
Bassham, Diane C. ;
Bergamini, Ettore ;
Bi, Xiaoning ;
Biard-Piechaczyk, Martine ;
Blum, Janice S. ;
Breclesen, Dale E. ;
Brodsky, Jeffrey L. ;
Brumell, John H. ;
Brunk, Ulf T. ;
Bursch, Wilfried ;
Camougrand, Nadine ;
Cebollero, Eduardo ;
Cecconi, Francesco ;
Chen, Yingyu ;
Chin, Lih-Shen ;
Choi, Augustine ;
Chu, Charleen T. ;
Chung, Jongkyeong ;
Clarke, Peter G. H. ;
Clark, Robert S. B. ;
Clarke, Steven G. ;
Clave, Corinne ;
Cleveland, John L. ;
Codogno, Patrice ;
Colombo, Maria I. ;
Coto-Montes, Ana ;
Cregg, James M. ;
Cuervo, Ana Maria ;
Debnath, Jayanta ;
Demarchi, Francesca ;
Dennis, Patrick B. ;
Dennis, Phillip A. ;
Deretic, Vojo ;
Devenish, Rodney J. ;
Di Sano, Federica ;
Dice, J. Fred ;
DiFiglia, Marian ;
Dinesh-Kumar, Savithramma ;
Distelhorst, Clark W. .
AUTOPHAGY, 2008, 4 (02) :151-175
[22]   Autophagy: from phenomenology to molecular understanding in less than a decade [J].
Klionsky, Daniel J. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (11) :931-937
[23]  
Kojima T, 1998, J PATHOL, V184, P212, DOI 10.1002/(SICI)1096-9896(199802)184:2<212::AID-PATH996>3.0.CO
[24]  
2-Z
[25]   Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons [J].
Komatsu, M. ;
Ueno, T. ;
Waguri, S. ;
Uchiyama, Y. ;
Kominami, E. ;
Tanaka, K. .
CELL DEATH AND DIFFERENTIATION, 2007, 14 (05) :887-894
[26]   Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice [J].
Komatsu, Masaaki ;
Waguri, Satoshi ;
Koike, Masato ;
Sou, Yu-shin ;
Ueno, Takashi ;
Hara, Taichi ;
Mizushima, Noboru ;
Iwata, Jun-ichi ;
Ezaki, Junji ;
Murata, Shigeo ;
Hamazaki, Jun ;
Nishito, Yasumasa ;
Iemura, Shun-ichiro ;
Natsume, Tohru ;
Yanagawa, Toru ;
Uwayama, Junya ;
Warabi, Eiji ;
Yoshida, Hiroshi ;
Ishii, Tetsuro ;
Kobayashi, Akira ;
Yamamoto, Masayuki ;
Yue, Zhenyu ;
Uchiyama, Yasuo ;
Kominami, Eiki ;
Tanaka, Keiji .
CELL, 2007, 131 (06) :1149-1163
[27]   Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways:: One for soluble Z variant of human α-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ [J].
Kruse, KB ;
Brodsky, JL ;
McCracken, AA .
MOLECULAR BIOLOGY OF THE CELL, 2006, 17 (01) :203-212
[28]   A TYPE-I COLLAGEN REPORTER GENE CONSTRUCT FOR PROTEIN ENGINEERING STUDIES - FUNCTIONAL EQUIVALENCE OF TRANSFECTED REPORTER COL1A1 AND ENDOGENOUS GENE-PRODUCTS DURING BIOSYNTHESIS AND IN-VITRO EXTRACELLULAR-MATRIX ACCUMULATION [J].
LAMANDE, SR ;
BATEMAN, JF .
BIOCHEMICAL JOURNAL, 1993, 293 :387-394
[29]   Procollagen folding and assembly:: The role of endoplasmic reticulum enzymes and molecular chaperones [J].
Lamandé, SR ;
Bateman, JF .
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 1999, 10 (05) :455-464
[30]   Studying protein dynamics in living cells [J].
Lippincott-Schwartz, J ;
Snapp, E ;
Kenworthy, A .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2001, 2 (06) :444-456