Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin
Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 120(2023), 2 vom: 10. Jan., Seite e2212644120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thepsuwan, Pattaraporn [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.01.2023 Date Revised 21.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2212644120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM351069186 |
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| 100 | 1 | |a Thepsuwan, Pattaraporn |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 21.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a SEL1L-HRD1 ERAD | |
| 650 | 4 | |a ceruloplasmin | |
| 650 | 4 | |a hepatocytes | |
| 650 | 4 | |a iron metabolism | |
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| 700 | 1 | |a Bhattacharya, Asmita |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Zhenfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Hippleheuser, Stephen |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Shaobin |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Xiaoqiong |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Nupur K |e verfasserin |4 aut | |
| 700 | 1 | |a Sierra, Mariana |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Juncheng |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Deyu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yu-Ming M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Kezhong |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Yatrik M |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Shengyi |e verfasserin |4 aut | |
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