Editors' ChoiceInnate Immunity

Hippo-sized antiviral defenses

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Science Signaling  11 Apr 2017:
Vol. 10, Issue 474, eaan4043
DOI: 10.1126/scisignal.aan4043

The Hippo signaling pathway modulates the strength of antiviral responses according to nutritional status or cell density.

Detection of cytosolic nucleic acids during viral infection triggers innate immune responses involving the kinase TBK1, which requires Lys63-linked ubiquitylation to become activated. TBK1 subsequently interacts with and phosphorylates the adaptor proteins STING and MAVS. The phosphorylated adaptor proteins recruit the transcription factor IRF3, which becomes activated upon phosphorylation by TBK1 and transcriptionally activates interferon-encoding genes. Zhang et al. (see also Muñoz-Wolf and Lavelle) investigated crosstalk between antiviral responses and responses to nutritional stress and increased cell-cell contact mediated by the Hippo signaling pathway. Activation of this pathway leads to phosphorylation of the transcriptional coactivators YAP and TAZ by the kinase LATS1/2, thereby blocking nuclear translocation or triggering degradation of these transcriptional coactivators. When not inhibited by the Hippo pathway, YAP/TAZ promote the expression of genes involved in proliferation and survival. Serum starvation and cell crowding increased the activity of an IRF3 transactivation reporter in Sendai virus–infected cells or in cells exposed to viral components, effects that were blocked by deficiency of LATS1 and LATS2. IRF3 reporter activity and TBK1 activation were decreased by overexpression of YAP or TAZ and were enhanced by knockdown of YAP or TAZ. The inhibition of TBK1 by YAP did not require its transcriptional activity. Instead, YAP blocked the Lys63-linked ubiquitylation of TBK1, preventing its activation, interaction with STING and MAVS, and phosphorylation of the adaptor proteins and IRF3. In vitro assays indicated that the transactivation domain of YAP inhibited the kinase activity of TBK1. Infection by two different viruses was decreased in cell lines deficient in YAP and TAZ and increased by overexpression of LATS1/2, and overexpression of a transcriptionally inactive form of human YAP in zebrafish embryos increased mortality from vesicular stomatitis viral infection. Thus, the Hippo signaling pathway modulates the strength of antiviral responses according to nutritional status or cell density.

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