IRF8 regulates intrinsic ferroptosis through repressing p53 expression to maintain tumor cell sensitivity to cytotoxic T lymphocytes
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ABSTRACT:
PROVIDER: PRJNA882793 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21658589_1.fastq.gz | Fastqsanger.gz | |||
| SRR21658589_2.fastq.gz | Fastqsanger.gz | |||
| SRR21658590_1.fastq.gz | Fastqsanger.gz | |||
| SRR21658590_2.fastq.gz | Fastqsanger.gz | |||
| SRR21658591_1.fastq.gz | Fastqsanger.gz |
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Project description:Ferroptosis has emerged as a cytotoxic T lymphocyte (CTL)-induced tumor cell death pathway. The regulation of tumor cell sensitivity to ferroptosis is still incompletely understood. We report here that the interferon regulatory factor 8 (IRF8) functions as a regulator of tumor cell intrinsic ferroptosis. Genome-wide gene expression profiling identified ferroptosis pathway as an IRF8-regulated pathway in tumor cells. IRF8.KO tumor cells acquire resistance to intrinsic ferroptosis induction and IRF8-deficient tumor cells exhibit decreased ferroptosis in response to tumor-specific CTLs. Irf8 deletion increases p53 expression in tumor cells and knocking out p53 in IRF8.KO tumor cells restored tumor cell sensitivity to intrinsic ferroptosis induction. Furthermore, IRF8.KO tumor cells grew significantly faster than WT tumor cells in immune competent mice. To restore IRF8 expression in tumor cells, we designed and synthesized codon usage-optimized IRF8-encoding DNA to generate IRF8-encoding plasmid NTC9385R-mIRF8. Restoring IRF8 expression via a lipid nanoparticle-encapsulated NTC9385R-mIRF8 plasmid therapy suppressed established tumor growth in vivo. In human cancer patients, nivolumab responders have a significant higher IRF8 expression level in their tumor cells as compared to the non-responders. Our data determine that IRF8 represses p53 expression to maintain tumor cell sensitivity to intrinsic ferroptosis
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Project description:Lymphocyte activation and effector state differentiation critically depend on integration of multiple signals, including those from antigen, co-stimulatory ligand and cytokine receptors. Thus, discovery of molecular components and mechanisms underlying signal integration is vital for the understanding and control of adaptive immune responses. Stimulation of antigen receptors in lymphocytes leads to the activation of NFAT family transcription factors (TFs) as well as the inducible expression of the immune-selective IRFs, IRF4 and IRF8; the latter are differentially controlled by co-stimulatory ligand and cytokine receptor signaling. Despite their major overlapping functions in lymphocyte activation and differentiation, it has remained enigmatic if NFATs can perform signal integration with IRF4 and IRF8, via their cooperative assembly on composite genomic regulatory elements. Composite elements (CEs) provide a powerful means of signal integration by inducible TFs and despite their clear importance, CEs arguably remain the least explored elements within cis-regulomes. To test the above hypothesis, we deployed a generalizable computational strategy, which revealed a stereospecific NFAT-IRF composite element (NICE) motif that was enriched within active chromatin regions (H3K27Ac) of activated B and T lymphocytes. NICE containing DNA sequences promoted cooperative binding of NFATs with IRF4 or IRF8. Genomic analyses in activated B cells revealed co-dependent genes that undergo activation or repression and contain NICE motifs in their regulatory regions. Notably, NFATc2 and IRF8 form a positive feedforward loop and coordinately repress the Prdm1 gene by binding a NICE motif in a phylogenetically conserved region, thereby inhibiting extrafollicular plasma cell differentiation and promoting the germinal center fate of activated B cells. The NICE motif is also enriched in DNA sequences located in accessible chromatin of human lymphocytes, suggesting evolutionary conservation of its function. The cooperative assembly of NFAT family members with IRF4 and IRF8 on NICE motifs reveals a new genomic control mechanism that enables signal integration during lymphocyte activation and differentiation.
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Project description:Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery towards infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation amongst the most prominent pathways. By combining global protein lipidation and membrane lipid composition studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase.
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