ID: 116: Novel ULK1-mediated responses in interferon signaling

Abstract

Type I Interferons (IFNs) are cytokines that exhibit important anti-tumorigenic, anti-viral and immunomodulatory functions. Yet, the precise mechanisms and sequence of events by which IFNs activate different signaling pathways required to mediate such responses remain to be fully defined. We have found that engagement of Type I IFN receptor (IFNR) activates a novel pathway, possibly involving both PI3K-AKT-dependent and independent meditators, culminating in activation of the Unc-51-like kinase 1 (ULK1). Importantly, ULK1 kinase activity seems to cooperate with the MAPKKK-MKK3/6 signaling cascade for optimal IFN-induced activation of p38 MAPK and gene transcription of key interferon stimulated genes (ISGs). Moreover, we have now identified novel interactors of ULK1 during engagement of IFNR by mass spectrometry analysis, which reveal new IFN-triggered ULK1-mediated signaling pathways. Our studies have also established that ULK1 is essential for Type I IFN-induced antiviral and antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms (MPNs). Altogether, our findings have important clinical-translational implications, as modulation of the ULK1 activity may be used as an approach to selectively enhance the activity of IFNs in normal hematopoiesis and against malignant cells. An update on our ongoing studies and the putative interactive proteins of the pathway in the interferon system will be presented and discussed.