Carboxylation switch

Activation of mitochondrial antiviral signaling protein (MAVS) at the mitochondria membrane mediates both interferon (IFN) and apoptosis responses. In Science, Okazaki et al. show that carboxylation of MAVS enhances type I IFN responses and represses apoptosis. MAVS was carboxylated at residues Asp53, Glu70, Glu80 and Asp83 in its cytoplasmic domain, and knockdown of γ-glutamyl carboxylase (GGCX), a type II endoplasmic reticulum (ER) transmembrane protein that carboxylates extracellular or ER lumen proteins in a manner dependent on the GGCX cofactor vitamin K, reduced MAVS carboxylation. MAVS activation was associated with increased accumulation of a non-glycosylated, inverted GGCX protein at the ER membrane. Expression of carboxylation-mutant MAVS, deletion of GGCX or inhibition of vitamin K decreased IFNβ and increased caspase-3 in response to viral infection. The mitochondrial transport protein TOMM40 and the kinase PLK1 associated with carboxylation-mutant MAVS, but not wild-type MAVS, and increased caspase-3, but not IFNβ. Deletion of GGCX in neural, but not myeloid cells, and vitamin K inhibition or deficiency in mice infected with vesicular stomatitis virus (VSV) reduced type I IFN and increased VSV titers and caspase-3 activation in the brain of wild-type, but not MAVS-deficient mice. Thus, GGCX carboxylation of MAVS acts as a regulatory switch in virus-infected cells.

Original reference: Science https://doi.org/10.1126/science.adk9967 (2025)