Research ArticleCytokines

IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

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Science Signaling  20 Nov 2018:
Vol. 11, Issue 557, eaap9921
DOI: 10.1126/scisignal.aap9921

IFN-γ activates alternative pathways

The cytokine IFN-γ has potent antiviral activity, and the kinase ULK1 is a key initiator of cellular catabolism through autophagy. Saleiro et al. found that IFN-γ receptor stimulation activated an alternative ULK1-dependent pathway required for antiviral activity. IFN-γ activated a ULK1-dependent cascade that involved activation of the kinases MLK3 and ERK5. The kinase function of ULK1 was required for the transcription of IFN-stimulated genes independently of the autophagy mediators Beclin-1 and VPS34. These data suggest that autophagy-independent functions of ULK1 are important for IFN-γ–mediated resistance to infection.


It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)–mediated antiviral response. Here, we found that IFN-γ receptor stimulation also activated Unc-51–like kinase 1 (ULK1), an initiator of Beclin-1–mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ–dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

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