The latest information on the RIPK1 post-translational modifications and functions

Qiong, Wang; Fan, Danping; Xia, Yu; Ye, Qinbin; Xi, Xiaoyu; Zhang, Guoqiang; Xiao, Cheng

doi:10.1016/j.biopha.2021.112082

Cited by 33 publications

(23 citation statements)

References 148 publications

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“…RIPK1 is involved in the regulation of multiple signaling pathways, such as inflammation, apoptosis and necroptosis ( 13 , 14 ). Therefore, for the previously detected inhibitory effect of KW2449 on inflammation, it is difficult to tell whether it acts directly on RIPK1-mediated inflammation or by acting on necroptosis to reduce the release of inflammatory cytokines.…”

Section: Resultsmentioning

confidence: 99%

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis

Wang

et al. 2023

Front. Immunol.

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ObjectiveNecroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.MethodsThe plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis.ResultsThe plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1.ConclusionThese findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

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Section: Resultsmentioning

confidence: 99%

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis

Wang

et al. 2023

Front. Immunol.

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“…It contains a DD comprising a 112 amino acid (aa) C-terminal sequence, a serine/threonine KD comprising a 300 aa N-terminal sequence, and a central region between the KD and DD called the intermediate domain (ID), which mediates NF-κB activation. 21 The C-terminal DD mediates the interaction between RIP1 and other proteins containing a DD (or homologous to a DD), such as factor-associated suicide (Fas), TNF-related apoptosis-inducing ligand receptor (TRAILR) 2, TRAILR1, and TNFR1, enabling RIP1 binding to these proteins, as well as TNFR1-associated death domain protein (TRADD) and Fas-associated death domain (FADD) in the TNFR1 signaling complex. The ID is important for NF-κB activation and RHIM-dependent signaling, and Lys63linked ubiquitination at Lys377 may be a crucial aa in the "ubiquitin code" because it interacts with many prosurvival ubiquitin-binding proteins (ubiquitin receptors) and leads to RIP1 mediation of cell survival in both NF-κB-dependent and NF-κB-independent manners.…”

Section: Rip1 Structure and Biological Functionsmentioning

confidence: 99%

“…RIP1 is a 76 kDa protein located on chromosome 6 and is composed of 671 amino acids. It contains a DD comprising a 112 amino acid (aa) C-terminal sequence, a serine/threonine KD comprising a 300 aa N-terminal sequence, and a central region between the KD and DD called the intermediate domain (ID), which mediates NF-κB activation . The C-terminal DD mediates the interaction between RIP1 and other proteins containing a DD (or homologous to a DD), such as factor-associated suicide (Fas), TNF-related apoptosis-inducing ligand receptor (TRAILR) 2, TRAILR1, and TNFR1, enabling RIP1 binding to these proteins, as well as TNFR1-associated death domain protein (TRADD) and Fas-associated death domain (FADD) in the TNFR1 signaling complex.…”

Section: Rip1 Structure and Biological Functions: Implications For Hu...mentioning

confidence: 99%

“…RIP1 is in a key position in the death receptor signaling pathway. It mediates signaling pathways related to cell survival and programmed cell death. , The function of RIP1 depends mostly on posttranslational modification. Multiple ubiquitination and phosphorylation sites that are individually or simultaneously modified result in different functions of RIP1 in different signaling pathways.…”

Section: Rip1 Structure and Biological Functions: Implications For Hu...mentioning

confidence: 99%

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Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

et al. 2022

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As a serine/threonine protein kinase, receptor-interacting protein 1 (RIP1) plays an important role in regulating the pathways in programmed cell death. Multifaceted human diseases (e.g., autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and tumors) are closely related to RIP1 kinase. Therefore, small-molecule RIP1 inhibitors with precise targeting and good penetrability have recently been used in potentially therapeutic methods, attracting extensive researcher interest. GSK2982772, developed by GlaxoSmithKline (GSK), became the world’s first RIP1 inhibitor approved for clinical research in 2014. Nine clinical trials assessing GSK2982772 have been performed. The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents.

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“…Recent evidence indicate that the switch between pro-survival and pro-death functions of RIPK1 is regulated by a panel of modifications including phosphorylation and ubiquitination (Wang, Fan et al, 2021) and the presence of kinase checkpoints in RIPK1 activation revealed the presence of multiple stages in the maturation of the complex IIb/ripoptosome (Amin, Florez et al, 2018). To understand the assembly and maturation of the ripoptosome into an active death inducer, it is important to identify novel ripoptosome interactors.…”

Section: Introductionmentioning

confidence: 99%

PRMT5-mediated regulatory arginine methylation of RIPK3

Chauhan

Val

Niedenthal

et al. 2022

Preprint

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The TNF receptor-interacting protein kinases (RIPK)-1 and 3 are regulators of extrinsic cell death response pathways, where RIPK1 makes the cell-survival or death decisions by associating with distinct complexes mediating survival signaling, caspase activation or RIPK3-dependent necroptotic cell death in a context dependent manner. Using a mass spectrometry-based screen to find new components of the ripoptosome/necrosome, we discovered the protein-arginine methyltransferase (PRMT)-5 as a direct interaction partner of RIPK1. Interestingly, RIPK3 but not RIPK1 was then found a target of PRMT5-mediated symmetric arginine dimethylation. A conserved arginine residue in RIPK3 (R486 in human, R415 in mouse) was identified as the evolutionarily conserved target for PRMT5-mediated symmetric dimethylation and the mutations R486A and R486K in human RIPK3 almost completely abrogated its methylation. Rescue experiments using these non-methylatable mutants of RIPK3 demonstrated PRMT5-mediated RIPK3 methylation to act as an efficient mechanism of RIPK3-mediated feedback control on RIPK1 activity and function. Therefore, this study reveals PRMT5-mediated RIPK3 methylation as a novel modulator of RIPK1-dependent signaling.

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The latest information on the RIPK1 post-translational modifications and functions

Cited by 33 publications

References 148 publications

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis

Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

PRMT5-mediated regulatory arginine methylation of RIPK3

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