Functional integrity of the SEL1L–HRD1 complex is critical for endoplasmic reticulum–associated degradation and organismal viability

TL;DR

The SEL1L–HRD1 complex is essential for protein quality control in cells and is critical for survival in mammals.

Contribution

This study demonstrates that direct SEL1L–HRD1 binding is essential for ERAD function and neonatal viability in mammals.

Findings

Mutations disrupting SEL1L–HRD1 binding lead to graded defects in protein clearance and survival.

The L709P mutation causes complete neonatal lethality by uncoupling ERAD pathway steps.

SEL1L–HRD1 interaction is required for ERAD complex formation and E2 enzyme recruitment.

Abstract

Endoplasmic reticulum–associated degradation (ERAD) is fundamental to cellular and organismal survival, yet the molecular determinants that enable a functional mammalian ERAD complex have remained unresolved. By combining mouse genetics with mechanistic studies, we show that direct binding between SEL1L and the E3 ligase HRD1 is indispensable for ERAD function and neonatal viability. Mutations that weaken or abolish this interaction produce graded defects in misfolded protein clearance and organismal survival. These findings define SEL1L–HRD1 association as an essential element of mammalian ERAD and illuminate how disruption of this interface contributes to early lethality and disease.

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.

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