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

Podocytes are key to kidney glomerular filtration barrier by forming slit diaphragm between interdigitating foot processes; however, molecular details and functional importance of protein folding and degradation in the ER remain unknown. Here we show that SEL1L-HRD1 protein complex of endoplasmic reticulum (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 shortly after weaning with impaired slit diaphragm, and die prematurely with a median life span of ~3 months. Mechanistically, we show that nephrin, a type-1 membrane protein causally linked to congenital nephrotic syndrome, is an endogenous ERAD substrate. ERAD deficiency attenuates the maturation of nascent nephrin, leading to its retention in the ER. Lastly, we show that various autosomal-recessive nephrin disease mutants are highly unstable and degraded by Sel1L-Hrd1 ERAD, which attenuates the pathogenicity of the mutants towards the wildtype allele. Hence, this study uncovers a critical role of Sel1L-Hrd1 ERAD in glomerular filtration barrier function and provides new insights into the pathogenesis associated with autosomal recessive disease mutants.