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PPDPF suppresses the development of hepatocellular carcinoma through TRIM21-mediated ubiquitination of RIPK1

ABSTRACT: Our study have shown that PPDPF promoted NF-κB activation through TRIM21-mediated K63-linked ubiquitination of RIPK1 in hepatocytes. Upon TNF-α stimulation, PPDPF enhances TRIM21/RIPK1 interaction and increases TRIM21-mediated K63-linked ubiquitination of RIPK1, which promotes NF-κB activation.To map the ubiquitination site of RIPK1 regulated by PPDPF, we performed MS analysis using control and RIPK1-overexpressing HEK293T cells with or without PPDPF overexpression

ORGANISM(S): Homo Sapiens

SUBMITTER: Jingjing Li

PROVIDER: PXD040301 | iProX | Tue Feb 21 00:00:00 GMT 2023

REPOSITORIES: iProX

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TRAF6, a master activator of p53 transactivation, suppresses mitochondrial p53 and apoptosis

Project description:TRAF6 -/- thymi display defects in IR-induced p53 target gene expression and attenuate further enhancement of apoptosis upon IR treatment. TRAF6-mediated K63-linked ubiquitination of p53 at K24

2016-11-04 | GSE69730 | GEO

Palmitoylation licenses RIPK1 cytotoxicity in the TNF pathway

Project description:We identified S-palmitoylation as a licensing modification for RIPK1 kinase activity in the TNF pathway. We found that DHHC5 palmitoylates RIPK1 at Cys257 residue, a process dependent on K63-linked ubiquitination of RIPK1, in response to TNF stimulation.

2024-03-15 | PXD050636 | iProX

Ubiquitination profile of polarized macrophages

Project description:Previous studies linked mac activation with the ubiquitination (ub) status of key proteins in inflammatory signal pathways. Lysine-48 ub (K48-ub) of the NF-κB inhibitor (IκB), the final checkpoint of the NFκB pathway, leads to IκB degradation and consequent NF-κB-associated inflammation. In contrast, TRAF6, an upstream positive regulator of the NF-κB pathway, is modulated by K63-ub, leading to its conformational change and activation. However, a comprehensive analysis of ub profiles of polarized macs has not been reported. If a unique ub signature is associated with individual mac subsets is not known.

2020-08-06 | PXD018743 | Pride

TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP

Project description:The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap−/− macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap−/− myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.

2021-03-01 | E-MTAB-10103 | biostudies-arrayexpress

SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

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

A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogeniccell death

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

TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging

Project description:Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

2018-07-04 | GSE116613 | GEO

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

Next Generation Sequencing to check the enrichment of RIPK1/BAF on chromatin, RIPK1-dependent chromatin state and RIPK1-dependent transcriptome during inflammatory responses.

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

CD95/Fas suppresses NF-B activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism

Project description:CD95 expression is preserved in triple-negative breast cancers (TNBCs) and CD95 loss in these cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2) using an unbiased proteomic approach. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit RelA (p65) and KPC1, which acts as E3 ubiquitin-protein ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines, that could account for the immune landscape remodeling in TNBC cells

2021-12-06 | PXD027196 | Pride

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