Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.

ABSTRACT: Metabolic remodelling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved are unclear. Here we report that viral-infection-induced inflammatory stimulation causes a rewiring of the urea cycle and the tricarboxylic acid cycle metabolism in macrophages to form a cyclic pathway called the aspartate-argininosuccinate (AAS) shunt. Using RNA sequencing, unbiased metabolomics and stable isotope tracing, we found that fumarate generated from the AAS shunt is driven by argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance interf

SUBMITTER: Xia W 

PROVIDER: S-EPMC12055588 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature