ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1β cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1β release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:300 |
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| Enthalten in: |
The Journal of biological chemistry - 300(2024), 4 vom: 01. Apr., Seite 107120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sharma, Jyotsna [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.04.2024 Date Revised 27.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2024.107120 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369077148 |
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| 500 | |a Date Revised 27.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1β cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1β release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ORMDL3 | |
| 650 | 4 | |a cytokine | |
| 650 | 4 | |a inlfammasome | |
| 650 | 4 | |a interleukin-1β | |
| 650 | 4 | |a mitochondria | |
| 650 | 4 | |a mitochondrial-associated ER membrane | |
| 650 | 4 | |a ulcerative colitis | |
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| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Inflammasomes |2 NLM | |
| 650 | 7 | |a NLRP3 protein, human |2 NLM | |
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| 650 | 7 | |a ORMDL3 protein, mouse |2 NLM | |
| 650 | 7 | |a Dextran Sulfate |2 NLM | |
| 650 | 7 | |a 9042-14-2 |2 NLM | |
| 700 | 1 | |a Khan, Shaziya |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Nishakumari C |e verfasserin |4 aut | |
| 700 | 1 | |a Sahu, Shikha |e verfasserin |4 aut | |
| 700 | 1 | |a Raj, Desh |e verfasserin |4 aut | |
| 700 | 1 | |a Prakash, Shakti |e verfasserin |4 aut | |
| 700 | 1 | |a Bandyopadhyay, Pamela |e verfasserin |4 aut | |
| 700 | 1 | |a Sarkar, Kabita |e verfasserin |4 aut | |
| 700 | 1 | |a Bhosale, Vivek |e verfasserin |4 aut | |
| 700 | 1 | |a Chandra, Tulika |e verfasserin |4 aut | |
| 700 | 1 | |a Kumaravelu, Jagavelu |e verfasserin |4 aut | |
| 700 | 1 | |a Barthwal, Manoj Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Shashi Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Srivastava, Mrigank |e verfasserin |4 aut | |
| 700 | 1 | |a Guha, Rajdeep |e verfasserin |4 aut | |
| 700 | 1 | |a Ammanathan, Veena |e verfasserin |4 aut | |
| 700 | 1 | |a Ghoshal, Uday C |e verfasserin |4 aut | |
| 700 | 1 | |a Mitra, Kalyan |e verfasserin |4 aut | |
| 700 | 1 | |a Lahiri, Amit |e verfasserin |4 aut | |
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