2025年7月7日 / 最終更新日 : 2025年7月7日 ad_y ニュース

2025年 新着論文 20　細胞情報学分野から論文が発表されました

Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense

Science. 2025 Jul 3;389(6755):84-91. doi: 10.1126/science.adk9967. Epub 2025 Jul 3.

Authors

Tomohiko Okazaki  1   2   3 , Keiji Nozaki  2 , Nao Morimoto  1 , Yuta Otobe  4 , Riho Saito  2 , Shuntaro Abe  1 , Miyuki Okajima  2 , Hikari Yoshitane  3   4   5 , Tomohisa Hatta  6 , Shun-Ichiro Iemura  7 , Tohru Natsume  8 , Hidetaka Kosako  9 , Miwako Yamasaki  10 , Satoshi Inoue  11   12 , Takashi Kondo  13 , Haruhiko Koseki  13 , Yukiko Gotoh  2   14

Affiliations

  • 1 Institute for Genetic Medicine, Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • 2 Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
  • 3 Japan Science and Technology Agency (JST) Fusion Oriented Research for Disruptive Science and Technology (FOREST) Program, Kawaguchi, Japan.
  • 4 Circadian Clock Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
  • 5 Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan.
  • 6 Robotic Biology Institute, Inc., Tokyo, Japan.
  • 7 Translational Research Center, Fukushima Medical University, Fukushima, Japan.
  • 8 Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
  • 9 Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
  • 10 Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
  • 11 Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, Japan.
  • 12 Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan.
  • 13 Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Yokohama, Japan.
  • 14 International Research Center for Neurointelligence (WPI-IRCN), University of Tokyo, Tokyo, Japan.

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.

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