2025-07-04 北海道大学,東京大学,科学技術振興機構
<関連情報>
- https://www.hokudai.ac.jp/news/2025/07/ggcxk.html
- https://www.hokudai.ac.jp/news/pdf/250704_pr.pdf
- https://www.science.org/doi/10.1126/science.adk9967
GGCXの膜トポロジー反転による細胞質カルボキシル化が抗ウイルス防御を制御する Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense
Tomohiko Okazaki, Keiji Nozaki, Nao Morimoto, Yuta Otobe, […] , and Yukiko Gotoh
Science Published:3 Jul 2025
DOI:https://doi.org/10.1126/science.adk9967
Editor’s summary
The mitochondrial antiviral signaling (MAVS) protein is part of the cellular machinery that helps to protect mammalian cells from viral infection. Okazaki et al. found that the amino acids in MAVS are carboxylated, and this modification is dependent on γ-glutamyl carboxylase (GGC), a membrane protein found in the endoplasmic reticulum that can invert its orientation so that its active site faces the cytosol. In the presence of activating signals, the authors found that GGC-dependent carboxylation of MAVS stimulated cells to produce type 1 interferon but suppressed signals leading to apoptosis. Mice in which GGC was inhibited, either by genetic knock-out in neurons or by depleting its co-factor vitamin K, had dysregulated responses to viral infection of the brain. —Sarah H. Ross
Abstract
Mitochondrial antiviral signaling protein (MAVS) is an adaptor involved in antiviral immunity, but its regulation is not fully understood. We identified carboxylation of MAVS by vitamin K (VK)–dependent γ-glutamyl carboxylase (GGCX), which was unexpected owing to the reported membrane topology of GGCX. We found that GGCX could undergo topology inversion to carboxylate MAVS within the cytoplasm. This carboxylation enhanced the ability of MAVS to induce type I interferons while suppressing the induction of apoptosis. Genetic knockout of GGCX, a VK-free diet, or depletion of VK by inhibiting VK epoxide reductase 1 with warfarin increased viral susceptibility in mice. Thus, we identified a MAVS regulatory mechanism—the existence of cytoplasmic protein carboxylation and topological inversion of GGCX—and demonstrated how modulating VK levels may influence antiviral defense.
