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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]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE198218 | GEO | 2022/05/12

REPOSITORIES: GEO

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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

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

TAILS proteomics of murine pancreatic tumors

Project description:Aberrant proteolysis by cysteine cathepsins is implicated in carcinogenesis, but knowledge of cathepsin substrates mediating tumor-promoting or suppressing effects is limited. Here we characterize tumor proteome and in vivo cathepsin substrates using cathepsin knockout mice and the RIP1-Tag2 model of pancreatic islet carcinogenesis. Applying an unbiased systems-level proteomics approach, Terminal Amine Isotopic Labeling of Substrates (TAILS), we identified cysteine cathepsin B, H, L, S, Z substrates and their cleavage sites. Among 1,935 proteins and 1,114 N-termini identified by TAILS using 8-plex iTRAQ protein labeling, 145 neo-N-termini were significantly changed in one (55%) or more knockouts suggesting a lack of direct compensation at substrate level by other cathepsins. Most affected N-termini (56-83% for different cathepsins) represented degradative cathepsin activity, whereas 17-44% of neo-N termini represented stable proteolytic products in the tumors and were enriched for extracellular proteins. We identified candidate substrates for mediating signaling roles of cysteine cathepsins in tumorigenesis.

2016-08-08 | PXD003637 | Pride

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

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

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

Project description: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.

2023-05-23 | GSE229446 | 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

Project description: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

| PRJNA813301 | ENA

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress

Serratia bockelmannii strain:Rip1

Project description:Serratia bockelmannii strain:Rip1 Genome sequencing

| PRJNA674496 | ENA

Simultaneous substrate and ubiquitin modification recognition by bispecific antibodies allows detection of ubiquitinated RIP1 and RIP2

Project description:Ubiquitination is crucial for the dynamic regulation of diverse signaling pathways. To enhance understanding of ubiquitination mediated signaling, we generated a new class of bispecific antibodies which combine recognition of ubiquitination substrates and specific polyubiquitin linkages. RIP1-K63 or RIP1-linear (Lin) linkage polyubiquitin bispecific antibodies can detect linkage-specific RIP1 ubiquitination in cells and in tissues, and also reveal RIP1 ubiquitination by immunofluorescence. In a similar fashion, RIP2 ubiquitination with K63 or linear linkages can be specifically detected with RIP2-K63 and RIP2-Lin bispecific antibodies. Furthermore, using RIP2-K63 and RIP2- Lin bispecific antibodies we examined IBD patient samples and found prominent K63- linked and linear RIP2 ubiquitination in ulcerative colitis and Crohn's disease patient samples. We also developed a bispecific antibody (K63-Lin) that can simultaneously recognize K63-linked and linear ubiquitination in a variety of signaling pathways. Collectively, these bispecific antibodies provide a novel conceptual paradigm for potential future development of inflammatory markers.

2023-01-24 | MSV000091134 | MassIVE

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