| 描述信息 |
Metabolic remodeling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved remain obscure. Here we report that viral infection-induced inflammatory stimulation causes a rewiring of urea cycle and TCA cycle metabolism to form a new cyclic pathway, 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 the argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β (IFN-β) production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance IFN-β production through direct mitochondrial antiviral signaling protein (MAVS) succination and activation of the RIG-I-like receptor (retinoic acid-inducible gene-I-like receptor, RLR) signaling. Furthermore, patients with Ebola virus disease (EVD) exhibit increased ASS1 expression, and ASS1-deficient mice display suppressed macrophage interferon responses. Therefore, these findings demonstrate that fumarate can be produced from the viral inflammation-induced AAS shunt and is essential for antiviral innate immunity. |
