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Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis

Author

Listed:
  • Xiaoqiong Wei

    (University of Virginia, School of Medicine
    University of Michigan Medical School)

  • You Lu

    (University of Michigan Medical School
    University of Michigan Medical School)

  • Liangguang Leo Lin

    (University of Virginia, School of Medicine
    University of Michigan Medical School)

  • Chengxin Zhang

    (University of Michigan Medical School)

  • Xinxin Chen

    (University of Virginia, School of Medicine
    University of Michigan Medical School)

  • Siwen Wang

    (University of Michigan Medical School)

  • Shuangcheng Alivia Wu

    (University of Virginia, School of Medicine
    University of Michigan Medical School)

  • Zexin Jason Li

    (University of Virginia, School of Medicine
    University of Michigan Medical School)

  • Yujun Quan

    (University of Virginia, School of Medicine)

  • Shengyi Sun

    (School of Medicine)

  • Ling Qi

    (University of Virginia, School of Medicine
    University of Michigan Medical School)

Abstract

Endoplasmic reticulum-associated degradation (ERAD) plays indispensable roles in many physiological processes; however, the nature of endogenous substrates remains largely elusive. Here we report a proteomics strategy based on the intrinsic property of the SEL1L-HRD1 ERAD complex to identify endogenous ERAD substrates both in vitro and in vivo. Following stringent filtering using a machine learning algorithm, over 100 high-confidence potential substrates are identified in human HEK293T and mouse brown adipose tissue, among which ~88% are cell type-specific. One of the top shared hits is the catalytic subunit of the glycosylphosphatidylinositol (GPI)-transamidase complex, PIGK. Indeed, SEL1L-HRD1 ERAD attenuates the biogenesis of GPI-anchored proteins by specifically targeting PIGK for proteasomal degradation. Lastly, several PIGK disease variants in inherited GPI deficiency disorders are also SEL1L-HRD1 ERAD substrates. This study provides a platform and resources for future effort to identify proteome-wide endogenous substrates in vivo, and implicates SEL1L-HRD1 ERAD in many cellular processes including the biogenesis of GPI-anchored proteins.

Suggested Citation

  • Xiaoqiong Wei & You Lu & Liangguang Leo Lin & Chengxin Zhang & Xinxin Chen & Siwen Wang & Shuangcheng Alivia Wu & Zexin Jason Li & Yujun Quan & Shengyi Sun & Ling Qi, 2024. "Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44948-2
    DOI: 10.1038/s41467-024-44948-2
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
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