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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.

Competing Interests: Declaration of interests The authors declare no competing interests.

Titel:	PKCλ/ι inhibition activates an ULK2-mediated interferon response to repress tumorigenesis.
Autor/in / Beteiligte Person:	Linares, JF ; Zhang, X ; Martinez-Ordoñez, A ; Duran, A ; Kinoshita, H ; Kasashima, H ; Nakanishi, N ; Nakanishi, Y ; Carelli, R ; Cappelli, L ; Arias, E ; Yashiro, M ; Ohira, M ; Patel, S ; Inghirami, G ; Loda, M ; Cuervo, AM ; Diaz-Meco, MT ; Moscat, J
Zeitschrift:	Molecular cell, Jg. 81 (2021-11-04), Heft 21, S. 4509
Veröffentlichung:	Cambridge Ma : Cell Press ; <i>Original Publication</i>: Cambridge, Mass. : Cell Press, c1997-, 2021
Medientyp:	academicJournal
ISSN:	1097-4164 (electronic)
DOI:	10.1016/j.molcel.2021.08.039
Schlagwort:	Adult Aged Aged, 80 and over Animals Autophagy CD8-Positive T-Lymphocytes metabolism Carcinogenesis Cell Transformation, Neoplastic Colorectal Neoplasms mortality Cycloheximide chemistry Female HEK293 Cells Humans Immunophenotyping Interferon Regulatory Factor-3 metabolism Male Membrane Proteins metabolism Mice Middle Aged Neoplasm Transplantation Phosphorylation Prognosis Protein Serine-Threonine Kinases genetics Protein Serine-Threonine Kinases metabolism Transcription Factors Up-Regulation Colorectal Neoplasms metabolism Interferons metabolism Isoenzymes metabolism Protein Kinase C metabolism Protein Serine-Threonine Kinases physiology Signal Transduction
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Mol Cell] 2021 Nov 04; Vol. 81 (21), pp. 4509-4526.e10. <i>Date of Electronic Publication: </i>2021 Sep 23. MeSH Terms: Signal Transduction* ; Colorectal Neoplasms / metabolism ; Interferons / metabolism ; Isoenzymes / metabolism ; Protein Kinase C / metabolism ; Protein Serine-Threonine Kinases / *physiology ; Adult ; Aged ; Aged, 80 and over ; Animals ; Autophagy ; CD8-Positive T-Lymphocytes / metabolism ; Carcinogenesis ; Cell Transformation, Neoplastic ; Colorectal Neoplasms / mortality ; Cycloheximide / chemistry ; Female ; HEK293 Cells ; Humans ; Immunophenotyping ; Interferon Regulatory Factor-3 / metabolism ; Male ; Membrane Proteins / metabolism ; Mice ; Middle Aged ; Neoplasm Transplantation ; Phosphorylation ; Prognosis ; Protein Serine-Threonine Kinases / genetics ; Protein Serine-Threonine Kinases / metabolism ; Transcription Factors ; Up-Regulation References: Nature. 2006 Feb 9;439(7077):682-7. (PMID: 16382236) ; Cell Rep. 2015 Apr 28;11(4):605-17. (PMID: 25892232) ; Nat Rev Immunol. 2021 Feb;21(2):116-128. (PMID: 32820267) ; Nature. 2017 Dec 7;552(7683):116-120. 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(PMID: 31697809) Grant Information: R01 DK124308 United States DK NIDDK NIH HHS; R37 AG021904 United States AG NIA NIH HHS; P50 CA211024 United States CA NCI NIH HHS; R01 DK098408 United States DK NIDDK NIH HHS; R01 CA207177 United States CA NCI NIH HHS; R01 CA250025 United States CA NCI NIH HHS; R01 CA218254 United States CA NCI NIH HHS Contributed Indexing: Keywords: STING; ULK1/2; atypical PKC; autophagy; chaperone-mediated autophagy; colorectal cancer; immunosuppression; immunosurveillance; immunotherapy; interferon Substance Nomenclature: 0 (IRF3 protein, human) ; 0 (Interferon Regulatory Factor-3) ; 0 (Isoenzymes) ; 0 (Membrane Proteins) ; 0 (STING1 protein, human) ; 0 (Transcription Factors) ; 9008-11-1 (Interferons) ; 98600C0908 (Cycloheximide) ; EC 2.7.1.11 (Ulk2 protein, mouse) ; EC 2.7.11.1 (Protein Serine-Threonine Kinases) ; EC 2.7.11.1 (TBK1 protein, human) ; EC 2.7.11.1 (Ulk2 protein, human) ; EC 2.7.11.13 (Protein Kinase C) ; EC 2.7.11.13 (protein kinase C lambda) Entry Date(s): Date Created: 20210924 Date Completed: 20220107 Latest Revision: 20221105 Update Code: 20231215 PubMed Central ID: PMC8571054

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