Reconstitution of Irf5−/− BMDMs with wild-type IRF5 restored cytokine production, whereas the S430A mutant did not, even in the presence of the Oga inhibitor Thiamet G. These data show that the OGT–IRF5 axis, specifically IRF5 O-GlcNAcylation on S430, drives a cytokine storm in fulminant viral infections. The gene discussed is IRF5; the disease is viral infectious disease.