Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense

• 成果类型: Article
• 署名作者: Okazaki, Tomohiko; Nozaki, Keiji; Morimoto, Nao; Otobe, Yuta; Saito, Riho; Abe, Shuntaro; Okajima, Miyuki; Yoshitane, Hikari; Hatta, Tomohisa; Iemura, Shun-ichiro; Natsume, Tohru; Kosako, Hidetaka; Yamasaki, Miwako; Inoue, Satoshi; Kondo, Takashi; Koseki, Haruhiko; Gotoh, Yukiko
• 署名单位: Hokkaido University; University of Tokyo; Japan Science & Technology Agency (JST); Tokyo Metropolitan Institute of Medical Science; University of Tokyo; Fukushima Medical University; National Institute of Advanced Industrial Science & Technology (AIST); Tokushima University; Hokkaido University; Tokyo Metropolitan Institute of Gerontology; Saitama Medical University; RIKEN; University of Tokyo
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12586
• DOI: 10.1126/science.adk9967
• 发表日期: 2025-07-03
• 页码: 84-91
• 关键词: k-dependent carboxylase; nf-kappa-b; rig-i; adapter protein; gene-expression; induction; apoptosis; PATHWAY; ips-1; ACID

摘要

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 gamma-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.