γ-Glutamyl carboxylase (GGCX) is a transmembrane protein localized on the endoplasmic reticulum membrane that catalyzes vitamin K-dependent carboxylation of glutamate and aspartate residues in endoplasmic reticulum lumen proteins. Okazaki et al. have now revealed that GGCX is able to invert its membrane topology to carboxylate cytoplasmic substrates. Specifically, the cytoplasmic domain of mitochondrial antiviral signaling protein (MAVS) was identified as a substrate, suggesting a role for GGCX in antiviral defense. MAVS overexpression triggered GGCX topology inversion, resulting in loss of C-terminal GGCX glycosylation; MAVS and the unglycosylated GGCX were found to preferentially interact, which might stabilize the inversion.
MAVS regulates both interferon production and apoptosis in response to viral infection. Proteomics studies revealed a carboxylation-deficient MAVS mutant preferentially associated with mitochondria-localized proteins such as TOMM40, a subunit of the mitochondrial protein importer TOMM. TOMM40 overexpression led to enhanced caspase activation for apoptosis and reduced interferon expression, and TOMM40 knockdown blocked MAVS-mediated caspase activation but had little effect on interferon production, suggesting MAVS carboxylation as a switch between apoptosis and interferon signaling. Mouse studies showed that GGCX and vitamin K in the diet exhibited protective effects against viral infection. Thus, these results also provide a link between vitamin K and the immune response. The mechanism of the GGCX topology inversion remains unclear, as do other functional effects of MAVS carboxylation and other cytoplasmic substrates of GGCX and their associated processes.
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