Research ArticleInnate Immunity

HIPK2 is necessary for type I interferon–mediated antiviral immunity

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Science Signaling  19 Mar 2019:
Vol. 12, Issue 573, eaau4604
DOI: 10.1126/scisignal.aau4604

Interferons are also HIP

Type I interferons are innate immune cytokines that are required to establish cellular host defense. Cao et al. found that the kinase HIPK2, best known for its role as an activator of p53 during DNA damage, was necessary for resistance to viral infection and for type I interferon production in mice. Activated downstream of intracellular viral RNA recognition, HIPK2 interacted with and promoted the phosphorylation of the transcription factor ELF4, which is necessary for the transcription of Ifn-β. Nuclear translocation of the kinase and caspase-dependent cleavage of an autoinhibitory domain in HIPK2 were necessary for these effects. These data identify HIPK2 as a previously uncharacterized effector in the type I interferon cascade (see Focus by Best and Ponia).


Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser369, which enabled Ifn-b transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs.

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