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A new NO-independent immunomodulatory function for iNOS in regulating itaconate production via mitochondrial protein-protein interaction with IRG1

ABSTRACT: iNOS modulates itaconate metabolism by a novel conformation-dependent protein-protein interaction separate from iNOS-mediated NO generation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Macrophage

SUBMITTER: Svenja Hester

LAB HEAD: Dr. Mark J. Crabtree

PROVIDER: PXD048712 | Pride | 2026-02-20

REPOSITORIES: Pride

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			Action	DRS
	QE1388_MSQ2168_MCrabtree_1_KO_6334_M1.raw	Raw
	QE1388_MSQ2168_MCrabtree_1_KO_6334_MO.raw	Raw
	QE1388_MSQ2168_MCrabtree_1_KO_6609_M1.raw	Raw
	QE1388_MSQ2168_MCrabtree_1_KO_6609_MO.raw	Raw
	QE1388_MSQ2168_MCrabtree_1_KO_6610_M1.raw	Raw

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Project description:One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

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