Central Role of ULK1 in Type I Interferon Signaling

• Type I IFNs induce phosphorylation of ULK1 at serine 757
• ULK activity mediates transcriptional activation of ISGs and activation of p38 MAPK
• IFN-dependent activation of ULK1/2 is essential for generation of antiviral responses
• ULK1 is required for IFN-induced antineoplastic effects in MPN progenitors

SummaryWe provide evidence that the Unc-51-like kinase 1 (ULK1) is activated during engagement of the type I interferon (IFN) receptor (IFNR). Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE) and IFNγ activation site (GAS) elements and controls expression of key IFN-stimulated genes (ISGs). We identify ULK1 as an upstream regulator of p38α mitogen-activated protein kinase (MAPK) and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses.

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