Species-specific regulation of necroptosis by STK38-dependent RIPK1 phosphorylation
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Epithelial Cell, Cell Culture
SUBMITTER: 
Seongmi Kim
LAB HEAD: Jaewhan Song
PROVIDER: PXD066201 | Pride | 2026-07-10
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| HJ_20170525_JMH_phospho04_add.raw | Raw | |||
| HJ_20170525_JMH_phospho04_add_Human.xlsx | Xlsx | |||
| HJ_20170525_JMH_phospho04_add_Human_addpeptide.xlsx | Xlsx | |||
| checksum.txt | Txt |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:Receptor-interacting protein kinase 1(RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1g) to Complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1g fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g-/- mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo.
2021-10-26 | GSE176422 | GEO
Project description:Necroptosis is a type of cell death with excessive inflammation and organ damage in various human diseases. Although abnormal necroptosis is common in patients with neurodegenerative, cardiovascular, and infectious diseases, the mechanisms by which O-GlcNAcylation contributes to the regulation of necroptotic cell death are poorly understood. In this study, we reveal that O- GlcNAcylation of RIPK1 (receptor-interacting protein kinase1) was decreased in erythrocytes of the mouse injected with lipopolysaccharide, resulting in the acceleration of erythrocyte necroptosis through increased formation of RIPK1-RIPK3 complex. Mechanistically, we discovered that O- GlcNAcylation of RIPK1 at serine 331 in human (corresponding to serine 332 in mouse) inhibits 32 This is a provisional file, not the final typeset article phosphorylation of RIPK1 at serine 166, which is necessary for the necroptotic activity of RIPK1 and suppresses the formation of the RIPK1-RIPK3 complex in Ripk1 -/- MEFs. Thus, our study demonstrates that RIPK1 O-GlcNAcylation serves as a checkpoint to suppress necroptotic signaling in erythrocytes.
2023-06-06 | PXD042579 | Pride
Project description:RIPK1 is a master regulator of multiple cell death pathways, including apoptosis and necroptosis, and inflammation. Multiple RIPK1 inhibitors have been advanced into human clinical trials as new therapeutics for human inflammatory and neurodegenerative diseases, including ALS and AD. However, while the mechanism of cytosolic RIPK1 in control of cell death has been extensively investigated, how the activation of RIPK1 may promote transcription of proinflammatory cytokines is unclear as a nuclear function of RIPK1 has not been explored, nor is it clear if and how RIPK1 kinase activity may directly mediate inflammation independent of cell death. Here we show that nuclear RIPK1 is recruited by specific transcription factors and binds to the BAF complex on active enhancers and promoters marked by H3K4me1 and H3K27ac. Nuclear RIPK1 mediates the phosphorylation of SMARCC2, a key component of the BAF complex, to promote chromatin remodeling and the transcription of specific proinflammatory genes. Our results suggest that RIPK1 kinase serves a transcriptional coregulator in nucleus that can transmit extracellular stimuli to BAF complex to modulate the chromatin accessibility and directly regulate the transcription of specific genes involved in mediating inflammatory responses.
2022-07-13 | GSE179018 | GEO
Project description:Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and premature aging. Accumulation of progerin, a toxic isoform of lamin A, or prelamin A, the precursor protein of lamin A, is the major underlying cause of premature aging syndromes. However, the molecular mechanism that mediates premature aging remains poorly defined. Here we report that the accumulation of farnesylated forms of prelamin A at the nuclear lamina triggers RIPK1 kinase-dependent signaling that leads to inflammation and RIPK3-mediated necroptosis in multiple tissues of a mouse model of accelerated aging (Zmpste24-/- mice). We show that prelamin A recruits RIPK1 in the nucleus to facilitate its activation in response to TNFα stimulation. Inhibition of prelamin A farnesylation prevents its accumulation at the nuclear envelope, and consequently reduces RIPK1 activation and necroptosis. The causality of RIPK1-driven necroptosis and inflammation in premature aging was demonstrated by genetic inactivation of RIPK1 or knockout of RIPK3, which prevented the premature degeneration of multiple tissues and organs in Zmpste24-/- mice and significantly extended their longevity. Our findings provide in vivo proof of principle for the feasibility of inhibition of RIPK1 kinase to slow down the progression of physiological and pathological aging.
2025-12-31 | GSE183102 | GEO
Project description:RIPK1 is a key signaling molecule controlling cell death and inflammation through both scaffold and kinase functions of RIPK1. Human RIPK1 deficiency causes immunodeficiency and inflammatory diseases. Here we analyzed the functional roles of RIPK1 in CD4 T cells.
2022-02-27 | GSE197232 | GEO
Project description:The mechanism underlying RIPK1-driven cell death and inflammation, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.
2022-10-20 | GSE193509 | GEO
Project description:Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that co- ordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-kB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treat- ment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.
2024-05-23 | PXD043560 | Pride
Project description:The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we used mesenteric lymph node (mLN) cells of Ripk1 KO mice, Ripk1/Casp8 double KO mice and their respective wild types to investigate this.
2024-06-20 | GSE260973 | GEO
Project description:Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.
2022-10-12 | PXD036995 | Pride