@article{9cc4c01d2ed245b498fd08175b379f7c,
title = "Endoplasmic reticulum-associated degradation is required for nephrin maturation and kidney glomerular filtration function",
abstract = "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.",
author = "Sei Yoshida and Xiaoqiong Wei and Gensheng Zhang and O'Connor, {Christopher L.} and Mauricio Torres and Zhangsen Zhou and Liangguang Lin and Rajasree Menon and Xiaoxi Xu and Wenyue Zheng and Yi Xiong and Edgar Otto and Tang, {Chih Hang Anthony} and Rui Hua and Rakesh Verma and Hiroyuki Mori and Yang Zhang and Hu, {Chih Chi Andrew} and Ming Liu and Puneet Garg and Hodgin, {Jeffrey B.} and Shengyi Sun and Markus Bitzer and Ling Qi",
note = "Funding Information: We would like to thank Richard Wojcikiewicz for the HRD1 antibody. We thank Chengxin Zhang for technical assistance in depositing sequencing data. We thank members of the Arvan and Qi laboratories for their technical assistance and insightful discussions. We also thank the University of Michigan Comprehensive Cancer Center (UMCCC) Tissue Core, Advanced Genomics Core, Imaging Laboratory of Michigan Diabetes Research Center, the Microscopy Core of Biomedical Research Core Facilities, and the Michigan Center for Materials Characterization for their support. This work is supported by the NIH (1R01CA163910, to CCAH and 1R35GM136422, to YZ); the National Natural Science Foundation of China (81620108004 and 81830025, to ML); the National Center for Advancing Translational Sciences (NCATS), NIH (UL1TR002240, to MB); and the NIH (R01DK120330, 1R01DK120047, 1R35GM130292, and a pilot grant from P30DK081943, to LQ). SY is supported in part by a Frontiers Science Center for Cell Responses grant from Nankai University (C029205001). ZZ is supported by an American Diabetes Association (ADA) Postdoctoral Fellowship (1-19-PDF-093). Funding Information: We would like to thank Richard Wojcikiewicz for the HRD1 antibody. We thank Chengxin Zhang for technical assistance in depositing sequencing data. We thank members of the Arvan and Qi laboratories for their technical assistance and insightful discussions. We also thank the University of Michigan Comprehensive Cancer Center (UMCCC) Tissue Core, Advanced Genomics Core, Imaging Laboratory of Michigan Diabetes Research Center, the Microscopy Core of Biomedical Research Core Facilities, and the Michigan Center for Materials Characterization for their support. This work is supported by the NIH (1R01CA163910, to CCAH and 1R35GM136422, to YZ); the National Natural Science Foundation of China (81620108004 and 81830025, to ML); the National Center for Advancing Trans- lational Sciences (NCATS), NIH (UL1TR002240, to MB); and the NIH (R01DK120330, 1R01DK120047, 1R35GM130292, and a pilot grant from P30DK081943, to LQ). SY is supported in part by a Frontiers Science Center for Cell Responses grant from Nankai University (C029205001). ZZ is supported by an American Diabetes Association (ADA) Postdoctoral Fellowship (1-19-PDF-093). Publisher Copyright: Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = apr,
day = "1",
doi = "10.1172/JCI143988",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",
}