Fumarate Strengthens the Antiviral Response of Macrophages
Macrophages alter their metabolism upon encountering pathogens, leading to the production of molecules that regulate immune responses. One such molecule is fumarate. Previous research demonstrated that fumarate promotes type I interferon (IFN-I) production when macrophages are activated by bacterial lipopolysaccharide (LPS).
The Nature Microbiology study revealed that viruses can also elevate fumarate levels in macrophages, which occurs via activation of the aspartate–argininosuccinate shunt, a metabolic pathway in which the enzyme argininosuccinate synthase 1 (ASS1) plays a key role. ASS1 enables fumarate production in the cytosol. Fumarate chemically modifies MAVS, the central signaling adaptor of the antiviral pathway, thereby stimulating the synthesis of IFN-α.
Experiments with vesicular stomatitis virus (VSV) have shown that infected macrophages reroute tricarboxylic acid (TCA) cycle metabolites into the argininosuccinate shunt, leading to increased fumarate levels. Supplementation with fumarate or its derivatives (dimethyl and monomethyl fumarate) enhanced IFN-β mRNA expression. Interestingly, IFN-β itself further upregulated ASS1 activity, forming a positive feedback loop.
When researchers experimentally reduced ASS1 expression, cytosolic fumarate levels dropped (while mitochondrial fumarate remained unchanged), and IFN-β production declined. Consequently, VSV replicated more rapidly. Administration of dimethyl fumarate restored IFN-β production in ASS1-deficient cells.
Thus, activation of ASS1 and cytosolic fumarate accumulation help macrophages combat viral infection more effectively by boosting IFN-I responses.
Fumarate Directly Activates the Antiviral Signaling Protein MAVS
To understand how fumarate enhances the antiviral response, researchers analyzed the activity of key signaling proteins. Since lowering ASS1 did not affect mitochondrial fumarate levels, fumarate’s effects could not be explained by mitochondrial mechanisms previously described for bacterial LPS. Instead, fumarate acts through MAVS:
- Overexpression of MAVS, but not the RNA sensors RIG-I or MDA5, amplified dimethyl fumarate–induced IFN-β
- Phosphorylation of downstream proteins TBK1 and IRF3 was reduced in ASS1-deficient macrophages.
Therefore, ASS1 activity is essential, as it triggers MAVS activation, which in turn boosts macrophage antiviral responses. Fumarate chemically modifies MAVS by succinating its cysteine residues.
After VSV infection, this succination process increased. When cysteine was replaced with serine, MAVS lost its ability to induce IFN-β expression. This amino acid substitution also impaired MAVS aggregation, which is necessary for its antiviral function.
Treatment of MAVS with dimethyl fumarate enhanced its succination and aggregation; however, this effect was lost when cysteine residues were mutated. Under these conditions, MAVS–TBK1 interactions were reduced. Thus, MAVS functions as a fumarate sensor.
Similar findings were observed with other viruses, including the Sendai virus, influenza A virus, and herpes simplex virus type 1. In all cases, ASS1 expression increased, while its deficiency reduced IFN-β production. Comparable results were obtained in human macrophages.
Mouse experiments confirmed these findings: upon VSV infection, ASS1-deficient mice exhibited reduced IFN-β levels, higher viral loads in the lungs and spleen, and increased mortality. MAVS succination was reduced under these conditions. Administration of dimethyl fumarate restored IFN-β responses and alleviated disease severity. Blood samples from Ebola patients also showed increased ASS1 expression in monocytes.
Conclusion
Cytosolic fumarate accumulation, driven by ASS1, is a general macrophage response to viral infection. Metabolic reprogramming during infection or autoimmune disease leads to fumarate buildup, which acts as a key immune regulator by stimulating interferon expression:
- Through MAVS activation via the ASS1 pathway,
- Alternatively, by inhibiting fumarase, resulting in mitochondrial RNA/DNA release that promotes IFN-I production.
Therefore, fumarate may serve as a therapeutic target for infectious and autoimmune diseases. However, further research is needed to elucidate the mechanisms by which fumarate regulates macrophage responses fully.
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Reference
MAVS is a sensor of fumarate during antiviral immunity
