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ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response.
PLoS Pathogens ( IF 5.5 ) Pub Date : 2020-04-06 , DOI: 10.1371/journal.ppat.1008457 Xuan Zhong 1 , Lu Feng 1 , Ru Zang 1 , Cao-Qi Lei 1 , Qing Yang 1 , Hong-Bing Shu 1
PLoS Pathogens ( IF 5.5 ) Pub Date : 2020-04-06 , DOI: 10.1371/journal.ppat.1008457 Xuan Zhong 1 , Lu Feng 1 , Ru Zang 1 , Cao-Qi Lei 1 , Qing Yang 1 , Hong-Bing Shu 1
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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.
中文翻译：
ZFYVE1负调节MDA5-，但不调节RIG-I介导的先天抗病毒反应。
维甲酸诱导的基因-I（RIG-I）-样受体（RLR），包括RIG-I和黑色素瘤分化相关基因5（MDA5），可感知胞质病毒RNA并引发先天性抗病毒反应。RIG-I和MDA5如何进行差分调节仍然是个谜。在这项研究中，我们确定了鸟苷酸结合蛋白（GBP）和含锌指FYVE结构域的蛋白ZFYVE1是MDA5-的负调节剂，而不是RIG-I介导的先天抗病毒反应。ZFYVE1缺陷促进了MDA5-的表达，但不促进RIG-I介导的下游抗病毒基因的转录。与野生型小鼠相比，Zfyve1-/-小鼠受到MDA5感测的脑心肌炎病毒（EMCV）致死性的显着保护，而Zfyve1-/-和Zfyve1 + / +小鼠与RIG-I检测到的水泡性口炎病毒（VSV）诱发的死亡相当。从机械上讲，ZFYVE1与MDA5交互，但与RIG-I不交互。ZFYVE1结合病毒RNA，并降低了MDA5的配体结合和寡聚。这些发现表明，ZFYVE1通过抑制其配体结合和寡聚化而充当MDA5介导的先天免疫应答的特异性负调节剂。
更新日期：2020-04-06
中文翻译：
ZFYVE1负调节MDA5-，但不调节RIG-I介导的先天抗病毒反应。
维甲酸诱导的基因-I（RIG-I）-样受体（RLR），包括RIG-I和黑色素瘤分化相关基因5（MDA5），可感知胞质病毒RNA并引发先天性抗病毒反应。RIG-I和MDA5如何进行差分调节仍然是个谜。在这项研究中，我们确定了鸟苷酸结合蛋白（GBP）和含锌指FYVE结构域的蛋白ZFYVE1是MDA5-的负调节剂，而不是RIG-I介导的先天抗病毒反应。ZFYVE1缺陷促进了MDA5-的表达，但不促进RIG-I介导的下游抗病毒基因的转录。与野生型小鼠相比，Zfyve1-/-小鼠受到MDA5感测的脑心肌炎病毒（EMCV）致死性的显着保护，而Zfyve1-/-和Zfyve1 + / +小鼠与RIG-I检测到的水泡性口炎病毒（VSV）诱发的死亡相当。从机械上讲，ZFYVE1与MDA5交互，但与RIG-I不交互。ZFYVE1结合病毒RNA，并降低了MDA5的配体结合和寡聚。这些发现表明，ZFYVE1通过抑制其配体结合和寡聚化而充当MDA5介导的先天免疫应答的特异性负调节剂。
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