The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes
© 2023. The Author(s)..
Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms for ER proteins and aggregates, respectively; however, the crosstalk between these two pathways under physiological settings remains unexplored. Using adipocytes as a model system, here we report that SEL1L-HRD1 protein complex of ERAD degrades misfolded ER proteins and limits ER-phagy and that, only when SEL1L-HRD1 ERAD is impaired, the ER becomes fragmented and cleared by ER-phagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL, a key lipolytic enzyme and an endogenous SEL1L-HRD1 substrate) and certain ER chaperones. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process influenced by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a sequence of events centered around SEL1L-HRD1 ERAD to dispose of misfolded proteins in the ER of adipocytes, highlighting the profound cellular adaptability to misfolded proteins in the ER in vivo.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 30. Mai, Seite 3132 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Shuangcheng Alivia [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.3.2.27 |
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| Anmerkungen: |
Date Completed 01.06.2023 Date Revised 12.06.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-38690-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357558707 |
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| 100 | 1 | |a Wu, Shuangcheng Alivia |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms for ER proteins and aggregates, respectively; however, the crosstalk between these two pathways under physiological settings remains unexplored. Using adipocytes as a model system, here we report that SEL1L-HRD1 protein complex of ERAD degrades misfolded ER proteins and limits ER-phagy and that, only when SEL1L-HRD1 ERAD is impaired, the ER becomes fragmented and cleared by ER-phagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL, a key lipolytic enzyme and an endogenous SEL1L-HRD1 substrate) and certain ER chaperones. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process influenced by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a sequence of events centered around SEL1L-HRD1 ERAD to dispose of misfolded proteins in the ER of adipocytes, highlighting the profound cellular adaptability to misfolded proteins in the ER in vivo | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 700 | 1 | |a Shen, Chenchen |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Xiaoqiong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiawei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Siwen |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xinxin |e verfasserin |4 aut | |
| 700 | 1 | |a Torres, Mauricio |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, You |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Liangguang Leo |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Huilun Helen |e verfasserin |4 aut | |
| 700 | 1 | |a Hunter, Allen H |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Deyu |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Shengyi |e verfasserin |4 aut | |
| 700 | 1 | |a Ivanova, Magdalena I |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Ling |e verfasserin |4 aut | |
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