Functional integrity of the SEL1L-HRD1 complex is critical for endoplasmic reticulum-associated degradation and...

The SEL1L-HRD1 complex is the most conserved branch of endoplasmic reticulum-associated degradation (ERAD), yet whether SEL1L is strictly required for HRD1 function in mammals has remained unclear. Here, we show, using complementary in vivo and in vitro approaches, that direct SEL1L-HRD1 binding is essential for ERAD activity and neonatal survival. Three knock-in mouse models targeting this interface reveal a clear genotype-phenotype relationship: the L709P variant, which abolishes SEL1L-HRD1 association, causes complete neonatal lethality; the partially disruptive S658P variant results in partial lethality; and the P699T mutation preserves the interaction and yields normal viability. Mechanistically, our data show that the SEL1L-HRD1 interface is essential for ERAD complex formation and activity, enabling both substrate handoff and E2 enzyme recruitment, and that the L709P mutation effectively uncouples these core steps of the mammalian ERAD pathway. These findings establish SEL1L-HRD1 coupling as a core requirement for mammalian ERAD function and early postnatal viability.