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In-vitro gene signature of NHEK's treated with caspase inhibitor Q-VD-Oph or DMSO

ABSTRACT: In-vitro gene signature of NHEK's treated with caspase inhibitor Q-VD-Oph or DMSO

PROVIDER: PRJNA885441 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21753351_1.fastq.gz	Fastqsanger.gz
	SRR21753351_2.fastq.gz	Fastqsanger.gz
	SRR21753352_1.fastq.gz	Fastqsanger.gz
	SRR21753352_2.fastq.gz	Fastqsanger.gz
	SRR21753353_1.fastq.gz	Fastqsanger.gz

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Project description:RNA sequencing of wild-type or Interferon Alpha receptor 1 Knockout MEF cells treated with DMSO or the Broad-spectrum Caspase Inhibitor Q-VD-OPh The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify of a mechanism by which mitochondria and downstream pro-apoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response, and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a pro-inflammatory type of cell death. To determine whether the pharmacological inhibition of caspases could recapitulate the phenotype caused by genetic deficiencies, we treated WT MEFs with broad-spectrum inhibitors of caspases (Q-VD-OPH). The inhibitor induced an increased expression of ISGs, similar to the effect of caspase or Apaf-1 deficiency. Next, we compared the transcriptional changes induced by caspase inhibition in WT and IFNAR1 KO cells, which lack a critical subunit of the receptor for IFNα/β (Muller et al., 1994). We observed that the absence of the IFNAR receptor abrogated the transcriptional response of the cells to caspase inhibition by Q-VD-OPH, demonstrating the role of type I IFNs in this response. RNA was extracted from duplicate samples and libraries generated for sequencing using the directional RNA-Seq library prep at the Yale Center for Genome Analysis. Libraries were sequenced using a Hiseq2500 sequencer to generate 76bp single-end reads. Duplicate samples were analyzed for each condition.

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In-vitro gene signature of NHEK's treated with caspase inhibitor Q-VD-Oph or DMSO

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