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

Xiaoqiong Wei, You Lu, Liangguang Leo Lin, Chengxin Zhang, Xinxin Chen, Siwen Wang, Shuangcheng Alivia Wu, Zexin Jason Li, Yujun Quan, Shengyi Sun and Ling Qi ()
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Xiaoqiong Wei: University of Virginia, School of Medicine
You Lu: University of Michigan Medical School
Liangguang Leo Lin: University of Virginia, School of Medicine
Chengxin Zhang: University of Michigan Medical School
Xinxin Chen: University of Virginia, School of Medicine
Siwen Wang: University of Michigan Medical School
Shuangcheng Alivia Wu: University of Virginia, School of Medicine
Zexin Jason Li: University of Virginia, School of Medicine
Yujun Quan: University of Virginia, School of Medicine
Shengyi Sun: School of Medicine
Ling Qi: University of Virginia, School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44948-2

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