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Targeting TBK1 potentiates oncolytic virotherapy via RIPK1-ICAM1 mediated NK killing in chemo-resistant colorectal cancer [scRNA-seq]

ABSTRACT: Targeting TBK1 potentiates oncolytic virotherapy via RIPK1-ICAM1 mediated NK killing in chemo-resistant colorectal cancer [scRNA-seq]

PROVIDER: PRJNA1244527 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR32941121_1.fastq.gz	Fastqsanger.gz
	SRR32941121_2.fastq.gz	Fastqsanger.gz
	SRR32941122_1.fastq.gz	Fastqsanger.gz
	SRR32941122_2.fastq.gz	Fastqsanger.gz

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TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging

Project description:Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

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Mechanisms of caspase-8 suppression of the RIPK1-TBK1 axis in homeostatic type I interferon production and regulation

Project description:Type-I interferons (IFNs) are an essential component of the innate immune response that are upregulated in response to infection. However, a low level of basal, or tonic, IFN expression is also critical to maintain tissue homeostasis. While the regulation of type-I IFN production during infection is well studied, the mechanisms controlling this basal expression and its impacts on homeostasis remain enigmatic. Here, we report the role of caspase-8 as a negative regulator of type-I IFN production during homeostasis in vitro and in vivo. Caspase-8 deficiency led to hyperactivation of basal type-I IFN signaling across multiple cell types and tissues and provided naturally heightened resistance to viral infection with norovirus. Mechanistically, the absence of caspase-8 allowed for an interaction between RIPK1 and TBK1, leading to enhanced TBK1 activation and aberrant type-I IFN production under homeostatic conditions. Loss of RIPK1 in caspase-8–deficient cells normalized TBK1 phosphorylation, IFN production and IFN signaling, thereby sensitizing cells to viral infection-induced inflammasome activation and inflammatory cell death, PANoptosis. In vivo, the elevated type-I IFN signaling, as well as the previously established early onset lymphadenopathy at 8 weeks of age, in caspase-8–deficient mice were reduced upon deletion of RIPK1 or type-I IFN neutralization. Overall, our study identified a mechanism which constrains tonic type-I IFN production and signaling during homeostasis. These results advance our understanding of tissue homeostasis and IFN regulation in infectious, autoimmune and autoinflammatory diseases, providing new insights for the development of disease treatments.

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TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging

Project description:TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging

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TBK1 and IKKε protect target cells from IFNgamma-mediated inflammatory apoptosis

Project description:T cells produce interferon gamma (IFNγ), but it is unclear whether they can use IFNγ to directly kill target cells. Here, we report that tumor targets lacking TBK1 and IKKε are killed by IFNγ, which induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1 to trigger RIPK1-dependent apoptosis. Concurrent with apoptosis, IFNγ unexpectedly also induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. The two kinases normally function to inhibit IKKa/b activity and in their absence, IFNγ induces elevated expression of inflammatory genes. Thus, IFNγ can induce an inflammatory form of apoptosis that is normally suppressed by TBK1 and IKKε. These kinases regulate three responses: (1) induction of type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these intertwined functions so that cells infected by pathogens encoding TBK1/IKKε antagonists to block type I IFN expression will be killed by IFNγ-secreting T cells to generate an alternate NFκB-dependent inflammatory response.

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Transcription profiling of mouse wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses

Project description:B-DNA-induced gene expression profile in wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats; to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses. Experiment Overall Design: Total RNA was extracted from embryonic fibroblats transfected for 4 h with or without poly(dA-dT)-poly(dT-dA), after which cRNA was synthesized. Preparation of cRNA, hybridization and scanning of the microarray were done according to the manufacturer's instructions (Affymetrix). A microarray (MG U74A version 2; Affymetrix) was used with Microarray Suite software (version 5.0; Affymetrix) and GeneSpring software (Silicon Genetics).

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