SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex

Author:

Lin Liangguang LeoORCID,Wang Huilun Helen,Pederson Brent,Wei XiaoqiongORCID,Torres Mauricio,Lu YouORCID,Li Zexin Jason,Liu Xiaodan,Mao HanchengORCID,Wang Hui,Zhou Linyao Elina,Zhao ZhenORCID,Sun ShengyiORCID,Qi LingORCID

Abstract

AbstractThe SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD). Despite recent advances in both mouse models and humans, in vivo evidence for the importance of SEL1L in the ERAD complex formation and its (patho-)physiological relevance in mammals remains limited. Here we report that SEL1L variant p.Ser658Pro (SEL1LS658P) is a pathogenic hypomorphic mutation, causing partial embryonic lethality, developmental delay, and early-onset cerebellar ataxia in homozygous mice carrying the bi-allelic variant. Biochemical analyses reveal that SEL1LS658P variant not only reduces the protein stability of SEL1L, but attenuates the SEL1L-HRD1 interaction, likely via electrostatic repulsion between SEL1L F668 and HRD1 Y30 residues. Proteomic screens of SEL1L and HRD1 interactomes reveal that SEL1L-HRD1 interaction is a prerequisite for the formation of a functional HRD1 ERAD complex, as SEL1L is required for the recruitment of E2 enzyme UBE2J1 as well as DERLIN to HRD1. These data not only establish the disease relevance of SEL1L-HRD1 ERAD, but also provide additional insight into the formation of a functional HRD1 ERAD complex.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

National Ataxia Foundation

Publisher

Springer Science and Business Media LLC

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