The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

被引:314
作者
Park, Sung-Woo [1 ,3 ]
Zhen, Guohua [1 ,4 ]
Verhaeghe, Catherine [1 ]
Nakagami, Yasuhiro [1 ]
Nguyenvu, Louis T. [1 ]
Barczak, Andrea J. [1 ]
Killeen, Nigel [2 ]
Erle, David J. [1 ,2 ]
机构
[1] Univ Calif San Francisco, Lung Biol Ctr, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Program Immunol, San Francisco, CA 94143 USA
[3] Soonchunhyang Univ, Dept Internal Med, Bucheon Hosp, Puchon 420020, Kyeonggi Do, South Korea
[4] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Internal Med, Wuhan 430030, Hubei, Peoples R China
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
colitis; endoplasmic reticulum; mucin; goblet cell; protein processing; CANCER-CELL-LINES; ENDOPLASMIC-RETICULUM; ULCERATIVE-COLITIS; GENE-EXPRESSION; HUMAN HOMOLOG; MICE; MUCIN; FAMILY; METASTASIS; INFLAMMATION;
D O I
10.1073/pnas.0808722106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals, but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells. Here, we show that AGR2 is present within the ER of intestinal secretory epithelial cells and is essential for in vivo production of the intestinal mucin MUC2, a large, cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. Mice lacking AGR2 were viable but were highly susceptible to colitis, indicating a critical role for AGR2 in protection from disease. We conclude that AGR2 is a unique member of the PDI family, with a specialized and nonredundant role in intestinal mucus production.
引用
收藏
页码:6950 / 6955
页数:6
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