Human Norovirus NTPase Antagonizes Interferon-β Production by Interacting With IkB Kinase ε.

Zifeng Zheng,Ming Fu,Yalan Liu,Mudan Zhang,Yuncheng Li,Qinxue Hu,Sitang Gong

doi:10.3389/fmicb.2021.687933

Zifeng Zheng, Ming Fu + Show 5 more

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https://doi.org/10.3389/fmicb.2021.687933

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Human norovirus (HuNoV) is the leading cause of epidemic acute gastroenteritis worldwide. Type I interferons (IFN)-α/β are highly potent cytokines that are initially identified for their essential roles in antiviral defense. It was reported that HuNoV infection did not induce IFN-β expression but was controlled in the presence of IFN-β in human intestinal enteroids and a gnotobiotic pig model, suggesting that HuNoV has likely developed evasion countermeasures. In this study, we found that a cDNA clone of GII.4 HuNoV, the predominantly circulating genotype worldwide, inhibits the production of IFN-β and identified the viral NTPase as a key component responsible for such inhibition. HuNoV NTPase not only inhibits the activity of IFN-β promoter but also the mRNA and protein production of IFN-β. Additional studies indicate that NTPase inhibits the phosphorylation and nuclear translocation of interferon-regulatory factor-3 (IRF-3), leading to the suppression of IFN-β promoter activation. Mechanistically, NTPase interacts with IkB kinase ε (IKKε), an important factor for IRF-3 phosphorylation, and such interaction blocks the association of IKKε with unanchored K48-linked polyubiquitin chains, resulting in the inhibition of IKKε phosphorylation. Further studies demonstrated that the 1-179 aa domain of NTPase which interacts with IKKε is critical for the suppression of IFN-β production. Our findings highlight the role of HuNoV NTPase in the inhibition of IFN-β production, providing insights into a novel mechanism underlying how HuNoV evades the host innate immunity.

Highlights

Human norovirus (HuNoV) is a non-enveloped, single-stranded, positive-sense, RNA virus belonging to the caliciviridae family (Thorne and Goodfellow, 2014)
The structural proteins of HuNoV can be detected in cells transfected with HuNoV cDNA clone in Caco-2 cells (Oliveira et al, 2018)
To test whether K48-linked polyubiquitin chains synthesized by tripartite motif-containing 6 (TRIM6) have functional relevance, we examined the ability of NTPase in inhibiting IFN-β promoter activation induced by retinoic acid-inducible gene I (RIG-I)-IN in TRIM6 knockdown cells

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Human norovirus (HuNoV) is a non-enveloped, single-stranded, positive-sense, RNA virus belonging to the caliciviridae family (Thorne and Goodfellow, 2014). ORF1 encodes a nonstructural polyprotein that is cleaved by its own protease to generate at least six distinct proteins: p48, NTPase, p22, VPg, 3CLpro, and RdRP. ORF3 encodes the minor capsid protein VP2, locating inside the viral capsid (Lu et al, 2015). The NTPase protein is cleaved by the viral protease at the 331-696 aa of the ORF1-encoded polyprotein, resulting in a mature protein with a length of 366 aa and a molecular weight of 40 kDa (Belliot et al, 2003). HuNoV is the leading cause of epidemic gastroenteritis worldwide (Bull et al, 2010; Ahmed et al, 2014; Brown et al, 2017), resulting in high morbidity and mortality rates in infants, young children, and the elderly (Campillay-Veliz et al, 2020). Due to the lack of an efficient in vitro cell culture system and a suitable animal model, our current understanding of HuNoV infection and pathogenesis is largely limited

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