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Ripk3 signaling regulates the number and function of HSCs during stress and represses radiation-induced leukemia in mice

ABSTRACT: Ripk3 signaling regulates the number and function of HSCs during stress and represses radiation-induced leukemia in mice

PROVIDER: PRJNA578632 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10316362.fastq.gz	Fastqsanger.gz
	SRR10316362_1.fastq.gz	Fastqsanger.gz
	SRR10316362_2.fastq.gz	Fastqsanger.gz
	SRR10316363_1.fastq.gz	Fastqsanger.gz
	SRR10316363_2.fastq.gz	Fastqsanger.gz

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Ripk3 signaling regulates the number and function of HSCs during stress and represses radiation-induced leukemia in mice

Project description:We found that Ripk3 signaling selectively regulates both the number and function of hematopoietic stem cells (HSCs) during stress conditions and inhibits ionizing radiation (IR)-induced leukemia development in mice. During serial transplantation, which stimulates a chronic Ripk3 activation in HSCs, Ripk3 promotes the loss of HSCs via Mlkl-mediated necroptosis and impairs HSC function by inducing ROS-p38-p16 mediated senescence. In response to 6Gy of IR, which induces the activation of p53-p21-mediated cell cycle arrest/senescence in HSCs, Ripk3 is required for the activation of NF-κB and permits the survival of the senescent cells. However, in response to multiple low doses of IR (1.75 × 4), Ripk3 signaling inhibits leukemia development by inducing ROS-p38-p16-mediated senescence and repressing Ire1α-Xbp1-Dnajb8 UPR fitness in pre-leukemic stem cells (pre-LSCs) and also inducing Mlkl-dependent clearance of pre-LSCs. Mlkl deletion prevents IR-induced loss of HSCs and slightly accelerates leukemia development in mice, while Ripk3 deletion represses both necroptotic and senescence signals in pre-LSCs and significantly accelerates IR-induced leukemia development. Our study suggests that immediately after high dose IR, temporal inhibition of Ripk3-NF-κB signaling might help to prevent long-term residual damage (LT-RDs) in bone marrow by eliminating the IR-induced senescent HSCs. However, in response to low dose radiation, induced activation of Ripk3 signaling at the pre-leukemia stage might help to prevent the accumulation of mutant HSCs and the development of leukemia.

2022-06-29 | GSE139143 | GEO

Ripk3 signaling regulates HSCs during stress and represses radiation-induced leukemia in mice.

Project description:Receptor-interacting protein kinase 3 (Ripk3) is one of the critical mediators of inflammatory cytokine-stimulated signaling. Here we show that Ripk3 signaling selectively regulates both the number and the function of hematopoietic stem cells (HSCs) during stress conditions. Ripk3 signaling is not required for normal homeostatic hematopoiesis. However, in response to serial transplantation, inactivation of Ripk3 signaling prevents stress-induced HSC exhaustion and functional HSC attenuation, while in response to fractionated low doses of ionizing radiation (IR), inactivation of Ripk3 signaling accelerates leukemia/lymphoma development. In both situations, Ripk3 signaling is primarily stimulated by tumor necrosis factor-α. Activated Ripk3 signaling promotes the elimination of HSCs during serial transplantation and pre-leukemia stem cells (pre-LSCs) during fractionated IR by inducing Mlkl-dependent necroptosis. Activated Ripk3 signaling also attenuates HSC functioning and represses a pre-LSC-to-LSC transformation by promoting Mlkl-independent senescence. Furthermore, we demonstrate that Ripk3 signaling induces senescence in HSCs and pre-LSCs by attenuating ISR-mediated mitochondrial quality control.

| S-EPMC9213819 | biostudies-literature

RIPK3-dependent transcriptional program in flavivirus-infected neurons

Project description:Here, we characterize RIPK3-dependent transcriptional responses in cortical neurons following infection with neurotropic flaviviruses. Neurons were infected with either Zika virus (ZIKV) strain MR766 at an MOI of 0.1, West Nile virus (WNV) strain TX 2002-HC at an MOI of 0.001, or a saline mock solution. Neurons were derived from mice lacking RIPK3 expression (Ripk3-/-) or wildtype controls. These studies revealed a number of antiviral genes whose upregulation following viral infection is absent in neurons lacking RIPK3, a subset of which were validated using qRT-PCR.

2018-11-06 | GSE122121 | GEO

Idenitifying RIPK3 dependent genes in neurons expressing RIPK3-activatable system

Project description:The transcriptional potential of RIPK3 in a non-infectious system in neurons is unclear. Here we found that RIPK3 activation, independent of any upstream signals is sufficient to induce anti-viral transcription in neurons.

2025-05-07 | GSE280962 | GEO

Ubiquitylation of RIPK3 beyond-the-RHIM limits RIPK3 activity and cell death

Project description:Pathogen recognition receptors and TNF superfamily members engage Receptor Interacting Serine/threonine Kinase-3 (RIPK3) to activate programmed cell death, including MLKL-mediated necroptosis and caspase-8-dependent apoptosis. However, the post-translational control of RIPK3 signalling is not fully understood. Using mass-spectrometry, we identified a novel ubiquitylation site on murine RIPK3 beyond the RIP homotypic interaction motif (RHIM) on K469. Complementation of RIPK3-deficient cells with a Ripk3K469R mutant demonstrated that the decoration of RIPK3 K469 by ubiquitin limits both RIPK3-mediated caspase-8 activation and apoptotic killing, in addition to RIPK3 autophosphorylation and MLKL-mediated necroptosis. Unexpectedly, the overall ubiquitylation of mutant RIPK3K469R was enhanced, which largely resulted from additional RIPK3 ubiquitylation on K359. Loss of RIPK3 K359 ubiquitylation reduced RIPK3K469R hyper-ubiquitylation and limited the ability of Ripk3K469R/K469R to trigger enhanced killing. Ripk3K469R/K469R mice challenged with Salmonella displayed increased bacterial loads in the spleen and liver, with reduced IFN serum levels. Therefore, RIPK3 K469 ubiquitylation can function to prevent RIPK3 ubiquitylation on alternate lysine residues, which otherwise promote RIPK3 oligomerization and consequent cell death signalling.

2022-08-12 | PXD026533 | Pride

Transcriptional profiles of PA1 teratoma cells transfected by RIPK1, RIPK2, RIPK3, or RIPK4

Project description:RIPK4 but not the related kinases RIPK1, RIPK2, and RIPK3 caused similar transcriptional changes to Wnt3a. PA1 cells were transfected by 8ug RIPK1, RIPK2, RIPK3, or RIPK4 for 48h, RNA were extracted and sequenced.

2013-02-04 | E-GEOD-43362 | biostudies-arrayexpress

Assessing RIPK3 dependent genes in death-resistant and death-susceptible MEFs encoding activatable RIPK3-system

Project description:The full transcriptional RIPK3-dependent transcriptional potential in MEFs is unknown. Here, we found that RIPK3 is a dominant driver of anti-viral and inflammatory transcription in MEFs.

2025-05-07 | GSE281061 | GEO

IM015 - Influenza infection of C57BL6 and RIPK3 knock-out mice

Project description:This purpose of this experiment was to investigate the transcriptional differences between C57BL6, RIPK3 knock-out mice infected with influenza strain A/CA/04/2009 (H1N1) virus. Overview of Experiment: Groups of 6-8 week-old C57BL6 and RIPK3 knock-out mice were infected with influenza A/CA/04/2009 virus. Infections were done at 10^5 PFU or time-matched mock infected. Time points were 2 and 4 d.p.i. There were 2-3 animals/dose/time point. Lung samples were collected for virus load and transcriptional analysis. Weight loss and animal survival were also monitored.

2014-04-02 | E-GEOD-51526 | biostudies-arrayexpress

DNA copy number alterations in radiation-induced rat mammary carcinomas

Project description:To investigate DNA copy number changes in rat mammary carcinomas induced by ioizing radiation.

2021-08-01 | GSE160514 | GEO

DNA copy number alterations in radiation-induced rat renal carcinomas

Project description:To investigate DNA copy number changes in rat renal carcinomas induced by ionizing radiation.

2020-10-29 | GSE160419 | GEO