PKCλ/ι inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

Juan F. Linares, Xiao Zhang, Anxo Martinez-Ordoñez, Angeles Duran, Hiroto Kinoshita, Hiroaki Kasashima, Naoko Nakanishi, Yuki Nakanishi, Ryan Carelli, Luca Cappelli, Esperanza Arias, Masakazu Yashiro, Masaichi Ohira, Sanjay Patel, Giorgio Inghirami, Massimo Loda, Ana Maria Cuervo, Maria T. Diaz-Meco, Jorge Moscat

Research output: Contribution to journalArticlepeer-review

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 PKCλ/ι 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. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι 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 PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

Original languageEnglish (US)
Pages (from-to)4509-4526.e10
JournalMolecular Cell
Volume81
Issue number21
DOIs
StatePublished - Nov 4 2021

Keywords

  • atypical PKC
  • autophagy
  • chaperone-mediated autophagy
  • colorectal cancer
  • immunosuppression
  • immunosurveillance
  • immunotherapy
  • interferon
  • STING
  • ULK1/2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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