ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP
ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP
复制标题
ADP-核糖基转移酶 PARP11 通过单 ADP 核糖基化泛素 E3 连接酶 β-TrCP 调节干扰素抗病毒反应
DOI：
10.1038/s41564-019-0428-3
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发表时间：
2019-11-01
影响因子：
28.3
通讯作者：
Zheng, Hui
中科院分区：
文献类型：
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作者：
Guo, Tingting;Zuo, Yibo;Zheng, Hui
病毒感染的爆发是全球健康负担。虽然I型干扰素（IFN-1）具有广谱抗病毒作用，但其在宿主细胞中的抗病毒效力在很大程度上受到病毒的限制。如何提高IFN-I的抗病毒疗效仍有待探索。在这里，我们确定了ADP-核糖基转移酶聚（ADP-核糖）聚合酶家族成员11（PARP 11）作为IFN-I抗病毒功效的有效调节剂。PARP 11不限制由水泡性口炎病毒或仙台病毒诱导的IFN-1产生，但抑制IFN-1激活信号的强度。从机制上讲，PARP 11单ADP核糖基化泛素E3连接酶β-转导蛋白重复蛋白（β-TrCP）。β-TrCP的单ADP核糖基化促进IFN α/β受体亚基1（IFNAR 1）泛素化和降解。此外，PARP 11表达被病毒感染上调，包括水泡性口炎病毒、单纯疱疹病毒-1和甲型流感病毒，从而促进ADP-核糖基化介导的病毒逃避。我们进一步强调了重新利用临床ADP-核糖基化抑制剂的潜力。我们发现rucaparib可以靶向PARP 11以稳定IFNAR 1，因此表现出有效增强IFN-I信号传导和宿主抗病毒反应。因此，rucaparib使小鼠对病毒感染更具抵抗力。我们的研究更新了对β-TrCP如何调节其底物的理解，并可能为改善IFN抗病毒疗效提供可药用靶点。
Outbreaks of viral infections are a global health burden. Although type I interferon (IFN-I) exerts broad-spectrum antiviral effects, its antiviral efficacy in host cells is largely restricted by viruses. How the antiviral efficacy of IFN-I can be improved remains to be explored. Here, we identified the ADP-ribosyltransferase poly(ADP-ribose) polymerase family member 11 (PARP11) as a potent regulator of IFN-I antiviral efficacy. PARP11 does not restrict IFN-I production induced by vesicular stomatitis virus or Sendai virus but inhibits the strength of IFN-I-activated signalling. Mechanistically, PARP11 mono-ADP-ribosylates the ubiquitin E3 ligase beta-transducin repeat-containing protein (beta-TrCP). Mono-ADP-ribosylation of beta-TrCP promotes IFN alpha/beta receptor subunit 1 (IFNAR1) ubiquitination and degradation. Moreover, PARP11 expression is upregulated by virus infections, including vesicular stomatitis virus, herpes simplex virus-1 and influenza A virus, thus promoting ADP-ribosylation-mediated viral evasion. We further highlight the potential for repurposing clinical ADP-ribosylation inhibitors. We found that rucaparib can target PARP11 to stabilize IFNAR1 and therefore exhibits efficient enhancement of IFN-I signalling and the host antiviral response. Consequently, rucaparib renders mice more resistant to viral infection. Our study updates the understanding of how beta-TrCP regulates its substrates and may provide a druggable target for improving IFN antiviral efficacy.