Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-03 DOI:10.1126/science.adk9967

Tomohiko Okazaki, Keiji Nozaki, Nao Morimoto, Yuta Otobe, Riho Saito, Shuntaro Abe, Miyuki Okajima, Hikari Yoshitane, Tomohisa Hatta, Shun-ichiro Iemura, Tohru Natsume, Hidetaka Kosako, Miwako Yamasaki, Satoshi Inoue, Takashi Kondo, Haruhiko Koseki, Yukiko Gotoh

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引用次数: 0

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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GGCX的膜拓扑倒置介导细胞质羧化，用于抗病毒防御

线粒体抗病毒信号蛋白（MAVS）是参与抗病毒免疫的适配体，但其调控机制尚不完全清楚。我们发现了维生素K （VK）依赖性γ-谷氨酰羧化酶（GGCX）对MAVS的羧化作用，由于报道的GGCX的膜拓扑结构，这是意想不到的。我们发现GGCX可以在细胞质内进行拓扑反转以羧酸化MAVS。这种羧基化增强了MAVS诱导I型干扰素的能力，同时抑制了细胞凋亡的诱导。基因敲除GGCX，不含VK的饮食，或通过华法林抑制VK环氧化物还原酶1来消耗VK，会增加小鼠的病毒易感性。因此，我们确定了MAVS的调控机制——细胞质蛋白羧化和ggcx的拓扑倒置，并证明了调节VK水平如何影响抗病毒防御。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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