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

• Published in: Molecular cell 2021-11, Vol.81 (21), p.4509-4526.e10
• Main Authors: Linares, Juan F., Zhang, Xiao, Martinez-Ordoñez, Anxo, Duran, Angeles, Kinoshita, Hiroto, Kasashima, Hiroaki, Nakanishi, Naoko, Nakanishi, Yuki, Carelli, Ryan, Cappelli, Luca, Arias, Esperanza, Yashiro, Masakazu, Ohira, Masaichi, Patel, Sanjay, Inghirami, Giorgio, Loda, Massimo, Cuervo, Ana Maria, Diaz-Meco, Maria T., Moscat, Jorge
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; atypical PKC; Autophagy; Carcinogenesis; CD8-Positive T-Lymphocytes - metabolism; Cell Transformation, Neoplastic; chaperone-mediated autophagy; colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Cycloheximide - chemistry; Female; HEK293 Cells; Humans; Immunophenotyping; immunosuppression; immunosurveillance; immunotherapy; interferon; Interferon Regulatory Factor-3 - metabolism; Interferons - metabolism; Isoenzymes - metabolism; Male; Membrane Proteins - metabolism; Mice; Middle Aged; Neoplasm Transplantation; Phosphorylation; Prognosis; Protein Kinase C - metabolism; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Serine-Threonine Kinases - physiology; Signal Transduction; STING; Transcription Factors; ULK1/2; Up-Regulation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.08.039

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. [Display omitted] •Low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in CRC•PKCλ/ι loss inhibits intestinal tumorigenesis through IFN and CD8+ T cell recruitment•PKCλ/ι inactivation selectively stimulates ULK2 to promote TBK1-STING-IRF3 signaling•Macroautophagy activation by PKCλ/ι loss prevents CMA-dependent degradation of STING Linares et al. describe how PKCλ/ι loss activates intestinal epithelial ULK2 and leads to its accumulation by inhibiting its degradation by microautophagy. Activated ULK2 phosphorylates TBK1 to promote the STING-mediated IFN signaling that triggers a CD8+ anti-tumor response. Activation of macroautophagy by PKCλ/ι deficiency prevents STING degradation by chaperone-mediated autophagy.