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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE180224 | GEO | 2021/09/23

REPOSITORIES: GEO

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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.

2021-09-23 | GSE180223 | GEO

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

2021-09-23 | GSE180222 | GEO

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.

| S-EPMC8571054 | biostudies-literature

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

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

| PRJNA747044 | ENA

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

| PRJNA747048 | ENA

Trisomy 21 consistently activates the interferon response

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-29 | E-GEOD-79843 | biostudies-arrayexpress

Trisomy 21 consistently activates the interferon response

Project description:This SuperSeries is composed of the SubSeries listed below.

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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection

Project description:This SuperSeries is composed of the SubSeries listed below.

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Inhibition of cGAS-Mediated Interferon Response Facilitates Transgene Expression.

Project description:DNA transfection is often the bottleneck of research and gene therapy practices. To explore the mechanism regulating transgene expression, we investigated the role of the cGAS-STING signaling pathway, which induces type-I interferons in response to DNA. We confirmed that deletion of cGAS enhances transgene expression at the protein level by ~2- to 3-fold. This enhancement is inversely correlated with the expression of interferons and interferon stimulated genes (ISGs), which suppress expression of transfected genes at the mRNA level. Mechanistically, DNA transfection activates the cGAS-STING pathway and induces the expression of the OAS family proteins, leading to the activation of RNaseL and degradation of mRNA derived from transgenes. Administration of chemical inhibitors that block cGAS-mediated signaling cascades improves the expression of transgenes by ~1.5- to 3-fold in multiple cell lines and primary cells, including T cells. These data suggest that targeting the cGAS-STING pathway can improve transgene expression, and this strategy may be applied to gene therapy.

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