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Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.

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Title: Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
Authors: 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
Source: Science. 7/3/2025, Vol. 389 Issue 6755, p84-91. 8p.
Subjects: Antiviral agents, Carboxylation, Vitamin K, Cytoplasm, Mice
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. 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 FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
– Name: Author
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  Data: <searchLink fieldCode="AR" term="%22Okazaki%2C+Tomohiko%22">Okazaki, Tomohiko</searchLink><br /><searchLink fieldCode="AR" term="%22Nozaki%2C+Keiji%22">Nozaki, Keiji</searchLink><br /><searchLink fieldCode="AR" term="%22Morimoto%2C+Nao%22">Morimoto, Nao</searchLink><br /><searchLink fieldCode="AR" term="%22Otobe%2C+Yuta%22">Otobe, Yuta</searchLink><br /><searchLink fieldCode="AR" term="%22Saito%2C+Riho%22">Saito, Riho</searchLink><br /><searchLink fieldCode="AR" term="%22Abe%2C+Shuntaro%22">Abe, Shuntaro</searchLink><br /><searchLink fieldCode="AR" term="%22Okajima%2C+Miyuki%22">Okajima, Miyuki</searchLink><br /><searchLink fieldCode="AR" term="%22Yoshitane%2C+Hikari%22">Yoshitane, Hikari</searchLink><br /><searchLink fieldCode="AR" term="%22Hatta%2C+Tomohisa%22">Hatta, Tomohisa</searchLink><br /><searchLink fieldCode="AR" term="%22Iemura%2C+Shun-ichiro%22">Iemura, Shun-ichiro</searchLink><br /><searchLink fieldCode="AR" term="%22Natsume%2C+Tohru%22">Natsume, Tohru</searchLink><br /><searchLink fieldCode="AR" term="%22Kosako%2C+Hidetaka%22">Kosako, Hidetaka</searchLink><br /><searchLink fieldCode="AR" term="%22Yamasaki%2C+Miwako%22">Yamasaki, Miwako</searchLink><br /><searchLink fieldCode="AR" term="%22Inoue%2C+Satoshi%22">Inoue, Satoshi</searchLink><br /><searchLink fieldCode="AR" term="%22Kondo%2C+Takashi%22">Kondo, Takashi</searchLink><br /><searchLink fieldCode="AR" term="%22Koseki%2C+Haruhiko%22">Koseki, Haruhiko</searchLink><br /><searchLink fieldCode="AR" term="%22Gotoh%2C+Yukiko%22">Gotoh, Yukiko</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 7/3/2025, Vol. 389 Issue 6755, p84-91. 8p.
– Name: Subject
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  Data: <searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink><br /><searchLink fieldCode="DE" term="%22Carboxylation%22">Carboxylation</searchLink><br /><searchLink fieldCode="DE" term="%22Vitamin+K%22">Vitamin K</searchLink><br /><searchLink fieldCode="DE" term="%22Cytoplasm%22">Cytoplasm</searchLink><br /><searchLink fieldCode="DE" term="%22Mice%22">Mice</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: 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. 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 FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.adk9967
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      – Code: eng
        Text: English
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        PageCount: 8
        StartPage: 84
    Subjects:
      – SubjectFull: Antiviral agents
        Type: general
      – SubjectFull: Carboxylation
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      – SubjectFull: Vitamin K
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      – SubjectFull: Cytoplasm
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      – SubjectFull: Mice
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      – TitleFull: Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
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