Endoplasmic reticulum-associated degradation is required for nephrin maturation and kidney glomerular filtration function.

Autor:	Yoshida S; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.; State Key Laboratory of Medical Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin, China., Wei X; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Zhang G; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., O'Connor CL; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Torres M; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Zhou Z; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Lin L; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Menon R; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Xu X; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Zheng W; State Key Laboratory of Medical Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin, China., Xiong Y; Center for Molecular Medicine and Genetics, Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA., Otto E; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Tang CA; Houston Methodist Cancer Center, Houston Methodist Academic Institute, Houston, Texas, USA., Hua R; State Key Laboratory of Medical Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin, China., Verma R; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Mori H; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Zhang Y; Department of Computational Medicine and Bioinformatics and Department of Biological Chemistry and., Hu CA; Houston Methodist Cancer Center, Houston Methodist Academic Institute, Houston, Texas, USA., Liu M; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Garg P; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Hodgin JB; Department of Pathology and., Sun S; Center for Molecular Medicine and Genetics, Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA., Bitzer M; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Qi L; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2021 Apr 01; Vol. 131 (7).
DOI:	10.1172/JCI143988
Abstrakt:	Podocytes are key to the glomerular filtration barrier by forming a slit diaphragm between interdigitating foot processes; however, the molecular details and functional importance of protein folding and degradation in the ER remain unknown. Here, we show that the SEL1L-HRD1 protein complex of ER-associated degradation (ERAD) is required for slit diaphragm formation and glomerular filtration function. SEL1L-HRD1 ERAD is highly expressed in podocytes of both mouse and human kidneys. Mice with podocyte-specific Sel1L deficiency develop podocytopathy and severe congenital nephrotic syndrome with an impaired slit diaphragm shortly after weaning and die prematurely, with a median lifespan of approximately 3 months. We show mechanistically that nephrin, a type 1 membrane protein causally linked to congenital nephrotic syndrome, is an endogenous ERAD substrate. ERAD deficiency attenuated the maturation of nascent nephrin, leading to its retention in the ER. We also show that various autosomal-recessive nephrin disease mutants were highly unstable and broken down by SEL1L-HRD1 ERAD, which attenuated the pathogenicity of the mutants toward the WT allele. This study uncovers a critical role of SEL1L-HRD1 ERAD in glomerular filtration barrier function and provides insights into the pathogenesis associated with autosomal-recessive disease mutants.
Databáze:	MEDLINE
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