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The response of WT, ∆rip1, and ∆sigL strains of Mycobacterium tuberculosis to dipyridyl treatment

ABSTRACT: Mycobacterium tuberculosis is exposed to a variety of stresses during a chronic infection, as the immune system simultaneously produces bactericidal compounds and starves the pathogen for essential nutrients. The intramembrane protease, Rip1, plays an important role in the adaptation to these stresses, at least partially by the cleavage of membrane bound transcriptional regulators. Although Rip1 is known to be critical for surviving copper intoxication and nitric oxide exposure, these stresses do not fully account the regulatory protein’s essentiality during infection. In this work, we demonstrate that Rip1 is also necessary for growth in low iron and zinc conditions, similar to those imposed by the immune system. Using a newly generated library of sigma factor mutants, we show that the known regulatory target of Rip1, SigL, shares this defect. Transcriptional profiling under iron limiting conditions supported the coordinated activity of Rip1 and SigL and demonstrated that the loss of these proteins produces an exaggerated iron starvation response. These observations demonstrate that Rip1 coordinates several aspects of metal homeostasis and suggest that a Rip1- and SigL-dependent pathway is involved in the adaptation to the iron deficient environments encountered during infection.

ORGANISM(S): Mycobacterium tuberculosis H37Rv

PROVIDER: GSE229446 | GEO | 2023/05/23

REPOSITORIES: GEO

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RIP1 perturbation induces chondrocyte necroptosis and promotes osteoarthritis pathogenesis

Project description:Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 and its functional mechanism in osteoarthritis pathogenesis remains largely unknown. To identify molecular targets of RIP1 in chondrocytes, RNA sequencing was performed in chondrocytes treated with adenovirus expressing RIP1 or vector control. We found that 9857 genes were differentially expressed in chondrocytes after RIP1 overexpression. GO analysis indicated that DNA replication, chromosome segregation and regulation of cell cycle process were upregulated, while terms including cartilage development, skeletal system development, extracellular matrix organization, skeletal system morphogenesis, chondrocyte differentiation, collagen fibril organization and limb development were downregulated. Pathway analysis revealed that IL-17 signaling pathway, cell cycle, DNA replication, proteasome, TNF signaling pathway, cellular senescence and p53 signaling pathway were significantly upregulated by RIP1, meanwhile, ECM-receptor interaction, other glycan degradation and glycosaminoglycan degradation were downregulated. These results underscore the importance of RIP1 in OA by perturbing a series of essential events during disease progression such like cell cycle regulation, chondrocyte differentiation, inflammation and ECM remodeling.

2021-01-22 | GSE165219 | GEO

Serratia bockelmannii strain:Rip1

Project description:Serratia bockelmannii strain:Rip1 Genome sequencing

| PRJNA674496 | ENA

Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection

Project description:Histone deacetylases (HDACs), as important enzymes regulating acetylation, participate in a series of cell physiological process. Here we reported that HDAC3-deficient macrophages had elevated expression of multiple cathepsins and over-expressed cathepsins such as cathepsin B (CTSB) caused remarkable degradation of receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIP1), which resulted in reduced TNFα mediated NF-κB activation and inflammatory response. Consistent with these findings, mice with macrophage specific knockout of HDAC3 were impaired in inflammatory response and susceptible to pseudomonas aeruginosa infection. Thus, our studies uncovered important roles of HDAC3 in the regulation of cathepsin-mediated lysosomal degradation and RIP1-mediated inflammatory response in macrophages as well as in host defense against bacterial infection.

2022-05-12 | GSE197989 | GEO

Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection [ChIP-seq]

2022-05-12 | GSE198218 | GEO

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

Project description:Gene ontology analysis suggested that targeting RIP1 induced changes in diverse innate inflammatory processes. Ingenuity analysis demonstrated that pathwaysupregulated by RIP1i included both MAP kinase and PPAR signaling, whereas select apoptosis and phagocytosis pathways were inhibited.

2018-09-10 | GSE111626 | GEO

Synechococcus phage S-RIP1 strain:R2_2007

Project description:Synechococcus phage S-RIP1 isolate R2_2007 genome sequencing project

| PRJNA47637 | ENA

Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury

Project description:RIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders. For mass spectrometry experiment, please check the method section in the manuscript.

2020-12-21 | MSV000086623 | MassIVE

Autocrine IL6 activates the STAT3-DNMT axis to silence the TNFa-RIP1 necroptosis pathway to sustain myeloid-derived suppressor cell survival and accumulation

Project description:Massive accumulation of myeloid-derived suppressor cells (MDSCs) is a hallmark of cancer. It is well-known that proinflammatory mediators induce MDSC accumulation. However, the functions of cell death pathways in MDSC survival and the mechanism underlying regulation of cell death pathways in MDSCs are still elusive. Herein, we determined that DNA methylation sustains MDSC accumulation in tumor-bearing mice since pharmacological inhibition of DNMTs with Dacitabine abolished MDSC accumulation and activated antigen-specific cytotoxic T lymphocytes in tumor-bearing mice. Decreased MDSC accumulation is correlated with increased IRF8 expression in MDSCs. However, Dacitabine also abolished CD11b+Gr1+ MDSC-like cell accumulation in IRF8 KO mice, suggesting that DNA methylation regulates MDSC accumulation at the post lineage differentiation stage. Use of cell death pathway-selective inhibitors identified necroptosis as the target of DNA methylation in MDSCs. Genome-wide DNA bisulfite sequencing revealed that the promoter of Tnf is hypermethylated in tumor-induced MDSCs. Consequently, decitabine dramatically increased TNF level in MDSCs and neutralizing TNF significantly decreased Dacitabine-induced MDSC cell death. Recombinant TNF induced MDSC cell cells in a dose and RIP1-dependent manner. Inhibition of RIP1 or RIP3 did not decrease TNF expression in MDSCs. Our data determined that the TNF-RIP1 necroptosis pathway is responsible at least in part for MDSC accumulation and that the IL6-activated DNMTs hypermethylate Tnf to impair necroptosis pathway to maintain MDSC accumulation in cancer. Our data depict the IL6-STAT3-DNMT-TNFa-RIP1 necroptosis pathway as a molecular target for suppressing MDSC accumulation in cancer immunotherapy.

2020-08-01 | GSE144649 | GEO

RIP1 perturbation induces chondrocyte necroptosis and promotes osteoarthritis pathogenesis

Project description:RIP1 perturbation induces chondrocyte necroptosis and promotes osteoarthritis pathogenesis

| PRJNA693686 | ENA

Human SV80 Cells: Control vs. Caspase-8 knock down

Project description:Excessive responses to pattern-recognition receptors are prevented by regulatory mechanisms that affect the amounts, conformation, and associative properties of their signaling proteins. We report that signaling by the ribonucleic acid sensor RIG-I is restricted, in addition, by caspase-mediated cleavage that results in conversion of a signaling enhancer to a signaling inhibitor. RIP1 and caspase-8, two proteins known to mediate effects of receptors of the TNF/NGF family, are recruited to the RIG-I complex following viral infection, and serve in a coordinated manner antagonistic regulatory roles: conjugation of a ubiquitin chain to Lys-377 in RIP1 facilitates assembly of the RIG-I complex, but it also renders RIP1 susceptible to caspase-8-mediated cleavage, yielding an inhibitory RIP1 fragment. The dependence of RIP1 cleavage on the same molecular change as the one that facilitates RIG-I signaling allows for RIG-I signaling to be restricted in its duration without compromising its initial activation.

2011-02-07 | GSE23363 | GEO

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