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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

ABSTRACT: PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

PROVIDER: PRJNA747044 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15168731.fastq.gz	Fastqsanger.gz
	SRR15168732.fastq.gz	Fastqsanger.gz
	SRR15168733.fastq.gz	Fastqsanger.gz
	SRR15168734.fastq.gz	Fastqsanger.gz
	SRR15168735.fastq.gz	Fastqsanger.gz

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

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

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

Project description:PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [RNA-Seq]

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

Project description: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.

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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

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

Project description: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.

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Trisomy 21 consistently activates the interferon response

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FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells

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