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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

Tingting Guo, Yibo Zuo, Liping Qian, Jin Liu, Yukang Yuan, Kailin Xu, Ying Miao, Qian Feng, Xiangjie Chen, Lincong Jin, Liting Zhang, Chunsheng Dong, Sidong Xiong, Hui Zheng

Nat Microbiol. 2019 Nov;4(11):1872-1884.

PMID: 30988430

Abstract:

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 β-transducin repeat-containing protein (β-TrCP). Mono-ADP-ribosylation of β-TrCP promotes IFNα/β 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 β-TrCP regulates its substrates and may provide a druggable target for improving IFN antiviral efficacy.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413026	PARP11 Active human			Price

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