Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Nature communications - 15(2024), 1 vom: 22. Jan., Seite 659 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wei, Xiaoqiong [VerfasserIn] |
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| Links: |
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| Themen: |
GPI-Linked Proteins |
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| Anmerkungen: |
Date Completed 24.01.2024 Date Revised 10.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-024-44948-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367440512 |
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| 245 | 1 | 0 | |a Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Lu, You |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Liangguang Leo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Chengxin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xinxin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Siwen |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Shuangcheng Alivia |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zexin Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Quan, Yujun |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Shengyi |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Ling |e verfasserin |4 aut | |
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