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

Author

Listed:
  • 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
    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
    University of California San Francisco)

  • 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)

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.

Suggested Citation

  • 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 Su, 2024. "SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45633-0
    DOI: 10.1038/s41467-024-45633-0
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