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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [ATAC-Seq]

ABSTRACT: The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCl/i inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCl/i directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCl/i results in increased levels of enzymatically active ULK2 that by direct phosphorylation activates TBK1 to foster the activation of the STING-mediated IFN response. PKCl/i inactivation also triggers autophagy that prevents STING degradation by chaperone-mediated autophagy. Thus, PKCl/i is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single cell multiplex imaging and bioinformatics analysis demonstrated that low PKCl/i levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE180223 | GEO | 2021/09/23

REPOSITORIES: GEO

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