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

作者：Sei Yoshida, Xiaoqiong Wei, Gensheng Zhang, Christopher L. O’Connor, Mauricio Torres, Zhangsen Zhou, Liangguang Leo Lin, Rajasree Menon, Xiaoxi Xu, Wenyue Zheng, Yi Xiong, Edgar A. Otto, Chih-Hang Anthony Tang, Rui Hua, Rakesh Verma, Hiroyuki Mori, Yang Zhang, Chih‐Chi Andrew Hu, Ming Liu, Puneet Garg, Jeffrey B. Hodgin, Shengyi Sun, Markus Bitzer, Ling Qi · 发表于：Journal of Clinical Investigation · 年份：2021 · DOI：10.1172/jci143988 · 被引用次数：62 · 研究领域：Renal Diseases and Glomerulopathies、Biomedical Research and Pathophysiology、Genetic and Kidney Cyst Diseases

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.