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

Liangguang Leo Lin, Huilun Helen Wang, Brent Pederson, Xiaoqiong Wei, Mauricio Torres, You Lu, Zexin Jason Li, Xiaodan Liu, Hancheng Mao, Hui Wang, Linyao Elina Zhou, Zhen Zhao, Shengyi Sun () and Ling Qi ()
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Liangguang Leo Lin: University of Virginia, School of Medicine
Huilun Helen Wang: University of Virginia, School of Medicine
Brent Pederson: University of Michigan Medical School
Xiaoqiong Wei: University of Virginia, School of Medicine
Mauricio Torres: University of Michigan Medical School
You Lu: University of Michigan Medical School
Zexin Jason Li: University of Virginia, School of Medicine
Xiaodan Liu: Keck School of Medicine of University of Southern California
Hancheng Mao: University of Michigan Medical School
Hui Wang: University of Virginia, School of Medicine
Linyao Elina Zhou: University of Virginia, School of Medicine
Zhen Zhao: Keck School of Medicine of University of Southern California
Shengyi Sun: University of Virginia, School of Medicine
Ling Qi: University of Virginia, School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract The 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.

Date: 2024
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DOI: 10.1038/s41467-024-45633-0

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