ERK5 Signaling is Required for Type III IFN-mediated Mucosal Antiviral Responses

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ERK5 Signaling is Required for Type III IFN-mediated Mucosal Antiviral Responses

Authors

Bone, H.; Natour, D. S.; McFadden, M. I.; Karp, A.; Basu, A.; Keller, A.; Denz, P. J.; Collins, P. L.; Mihaylova, M. M.; Yount, J. S.; Forero, A.

Abstract

Type III interferons (IFN{lambda}) are innate immune cytokines that limit viral replication and coordinate tissue repair through the induction of interferon stimulated genes (ISGs). This response must be tightly regulated to avoid excessive responses that result in the disruption of tissue barrier integrity or inefficient responses that allow for pathogen escape. Here we examine the contribution of Mitogen Activated Protein Kinase (MAPK) signaling on IFN{lambda}-mediated antiviral activity. We find that extracellular-signal-regulated kinase 5 (ERK5), a poorly characterized member of the conventional MAPK family, potentiates the antiviral efficacy of IFN{lambda}. Chemical inhibition and genetic targeting of ERK5 during IFN{lambda} treatment of cells results in a decrease in ISG induction and impaired control of viral infections. This decrease in IFN{lambda} antiviral efficacy in the absence of ERK5 kinase activity corresponded to lowered STAT1 phosphorylation, revealing a noncanonical role for ERK5 in STAT1 activation downstream of IFN{lambda}. In contrast, type I IFN antiviral signaling is largely resistant to ERK5 modulation. Altogether, we identify ERK5 as a potentiator of STAT1 activation, ISG expression, and antiviral activity following type III IFN stimulation.

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