Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
PLoS Pathog. 2020 Apr 6;16(4):e1008457. doi: 10.1371/journal.ppat.1008457. eCollection 2020 Apr.
The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5), sense cytoplasmic viral RNA and initiate innate antiviral responses. How RIG-I and MDA5 are differentially regulated remains enigmatic. In this study, we identified the guanylate-binding protein (GBP) and zinc-finger FYVE domain-containing protein ZFYVE1 as a negative regulator of MDA5- but not RIG-I-mediated innate antiviral responses. ZFYVE1-deficiency promoted MDA5- but not RIG-I-mediated transcription of downstream antiviral genes. Comparing to wild-type mice, Zfyve1-/- mice were significantly protected from lethality induced by encephalomyocarditis virus (EMCV) that is sensed by MDA5, whereas Zfyve1-/- and Zfyve1+/+ mice were comparable to death induced by vesicular stomatitis virus (VSV) that is sensed by RIG-I. Mechanistically, ZFYVE1 interacted with MDA5 but not RIG-I. ZFYVE1 bound to viral RNA and decreased the ligand binding and oligomerization of MDA5. These findings suggest that ZFYVE1 acts as a specific negative regulator of MDA5-mediated innate immune responses by inhibiting its ligand binding and oligomerization.
视黄酸诱导基因-I（RIG-I）样受体（RLRs），包括 RIG-I 和黑色素瘤分化相关基因 5（MDA5），可识别细胞质中的病毒 RNA 并启动先天抗病毒反应。但是 RIG-I 和 MDA5 如何被差异化调节仍然是个谜。在这项研究中，我们鉴定了鸟嘌呤结合蛋白（GBP）和锌指 FYVE 结构域蛋白 ZFYVE1 是 MDA5 而不是 RIG-I 介导的先天抗病毒反应的负调节剂。ZFYVE1 缺失促进 MDA5 而不是 RIG-I 介导的下游抗病毒基因的转录。与野生型小鼠相比，Zfyve1-/- 小鼠对脑炎心肌炎病毒（EMCV）诱导的致死性有明显的保护作用，因为 EMCV 可被 MDA5 识别，而 Zfyve1-/- 和 Zfyve1+/+ 小鼠对水疱性口炎病毒（VSV）诱导的致死性无差异，因为 VSV 可被 RIG-I 识别。在机制上，ZFYVE1 与 MDA5 相互作用而不与 RIG-I 相互作用。ZFYVE1 与病毒 RNA 结合，并降低 MDA5 的配体结合和寡聚化。这些发现表明，ZFYVE1 通过抑制其配体结合和寡聚化，作为 MDA5 介导的先天免疫反应的特异性负调节剂发挥作用。
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