N-glycosylation in the protease domain of trypsin-like serine proteases mediates calnexin-assisted protein folding

Author:

Wang Hao12ORCID,Li Shuo1,Wang Juejin1,Chen Shenghan1,Sun Xue-Long1234ORCID,Wu Qingyu125ORCID

Affiliation:

1. Molecular Cardiology, Cleveland Clinic, Cleveland, United States

2. Department of Chemistry, Cleveland State University, Cleveland, United States

3. Chemical and Biomedical Engineering, Cleveland State University, Cleveland, United States

4. Center for Gene Regulation of Health and Disease, Cleveland State University, Cleveland, United States

5. Cyrus Tang Hematology Center, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China

Abstract

Trypsin-like serine proteases are essential in physiological processes. Studies have shown that N-glycans are important for serine protease expression and secretion, but the underlying mechanisms are poorly understood. Here, we report a common mechanism of N-glycosylation in the protease domains of corin, enteropeptidase and prothrombin in calnexin-mediated glycoprotein folding and extracellular expression. This mechanism, which is independent of calreticulin and operates in a domain-autonomous manner, involves two steps: direct calnexin binding to target proteins and subsequent calnexin binding to monoglucosylated N-glycans. Elimination of N-glycosylation sites in the protease domains of corin, enteropeptidase and prothrombin inhibits corin and enteropeptidase cell surface expression and prothrombin secretion in transfected HEK293 cells. Similarly, knocking down calnexin expression in cultured cardiomyocytes and hepatocytes reduced corin cell surface expression and prothrombin secretion, respectively. Our results suggest that this may be a general mechanism in the trypsin-like serine proteases with N-glycosylation sites in their protease domains.

Funder

National Institutes of Health

The National Science Foundation of China

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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