ArticleThe Journal of biological chemistry2024
ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.
Article in The Journal of biological chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 13 citations in OpenAlex.
- MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.Cellular & molecular biology letters · 2025Pooled it
- Deletion of the T1D risk geneBiochemistry and biophysics reports · 2026Article
- Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review).International journal of molecular medicine · 2026Review
- Mitochondrial Dysfunction in Ulcerative Colitis: Pathogenic Mechanisms and Novel Therapeutics.Journal of biochemical and molecular toxicology · 2026Review
- Hypothalamic ceramide metabolism in obesity and dysregulation of glucose homeostasis.Reviews in endocrine & metabolic disorders · 2026Review
- Role of mitochondrial translation in modulating inflammatory disease outcome: Current knowledge and future perspectives.The Journal of biological chemistry · 2026Review
- ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- DAPL1 restrains RPE PANoptosis in experimental AMD by inhibiting GRP75-mediated mitochondria-associated endoplasmic reticulum membranes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dysfunction of mitochondria in intestinal epithelial cells: a key player in the pathogenesis of inflammatory bowel diseases.Gastroenterology report · 2026Review
- Macrophage dysregulation in inflammatory bowel disease: cellular heterogeneity, pathogenic mechanism, and treatment.Frontiers in immunology · 2026Review
- The plasticity and metabolic reprogramming of macrophage in ulcerative colitis.Frontiers in immunology · 2026Review
- Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.Frontiers in nutrition · 2026Review
- Review
- Updated insights into the molecular networks for NLRP3 inflammasome activation.Cellular & molecular immunology · 2025Review
- Role of mitochondria-associated membranes (MAMs) in inflammatory signaling: implications for acute lung injury pathogenesis.Frontiers in cell and developmental biology · 2025Review
- Revealing the dance of NLRP3: spatiotemporal patterns in inflammasome activation.Immunometabolism (Cobham, Surrey) · 2025Review
- Modulation of Orosomucoid-like Protein 3 Activity in the Management of Inflammatory Bowel Disease.Journal of biotechnology and biomedicine · 2024Article
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Authors and funding
19 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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