Search results for RIPK1

Showing 13 results out of 160

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Protein (4 results from a total of 20)

Identifier: R-HSA-5212671
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: RIPK1: Q13546
Identifier: R-HSA-6783197
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: RIPK1: Q13546
Identifier: R-HSA-937021
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: RIPK1: Q13546
Identifier: R-HSA-6783308
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: RIPK1: Q13546

Reaction (4 results from a total of 71)

Identifier: R-HSA-9819106
Species: Homo sapiens
Compartment: cytosol
Autophagy controls programmed cell death through different cross-talk signals (Bray K et al. 2012; Goodall ML et al. 2016; Lim J et al 2019; Wu W et al. 2020). For instance, serine/threonine kinase Unc-51-like kinase-1 (ULK1), an essential initiator of the autophagy response, regulates the tumor necrosis factor α (TNFα)-induced signaling pathway (Wu W et al. 2020; reviewed in Zou L et al. 2022). TNFα binds TNF receptor 1 (TNFR1) inducing the sequential formation of several signaling complexes, namely complex I and complex IIa/b (Micheau O and Tschopp J 2003; Walczak H 2011; Yuan J et al. 2019). These complexes support either cell survival (complex I) or cell death (complex II). Receptor-interacting serine/threonine protein kinase 1 (RIPK1) functions as a key regulator of the TNF:TNFR1 signaling pathway (reviewed in Ju E et al. 2022). The RIPK1 activity is tightly regulated by proteolysis, ubiquitination and phosphorylation (reviewed in Delanghe T et al. 2020; Ju E et al. 2022). RIPK1 was identified as a substrate of ULK1 (Wu W et al. 2020). ULK1 deficiency enhanced autophosphorylation of RIPK1 at S166 and association of RIPK1 with FADD in TNF-stimulated mouse fibroblast L929 and MEF cells (Wu W et al. 2020). Co-immunoprecipitation assay showed that ULK1 associated with RIPK1 upon co-expression of tagged proteins in human embryonic kidney 293 (HEK293) cells (Wu W et al. 2020). The interaction between endogenous ULK1 and RIPK1 was detected in TNF-stimulated L929 cells. The kinase activity of ULK1 was found to phosphorylate RIPK1 at S357 in HEK293 (Wu W et al. 2020). The ULK1-mediated phosphorylation of RIPK1 occurred preferentially in the cytosol preventing the formation of complex II (Wu W et al. 2020). These data suggest that ULK1 exerts a cytoprotective function by suppressing RIPK1-mediated cell death.

This Reactome event describes ULK1-mediated phosphorylation of RIPK1 at S357 within the cytosolic TRAF2:TRADD:RIPK1 complex.

Identifier: R-HSA-9793679
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Ligation of TNF-α to TNF receptor 1 (TNFR1) induces the formation of the TNFR1 signaling complex composed of TNFR1, TRADD (TNFR1-associated death domain), TRAF2 (TNF receptor associated factor-2), RIPK1 (receptor-interacting serin/threonine protein kinase 1), and E3 ubiquitin ligases BIRC2, BIRC3 (cIAP1/2, cellular inhibitor of apoptosis) and LUBAC (linear ubiquitin chain assembly complex) (Micheau O and Tschopp J 2003). The conjugation of K63-linked ubiquitin (Ub) chains by BIRC2/3 to RIPK1 allows further recruitment and activation of the TAK1 (also known as MAP3K7) complex and IκB kinase (IKK) complex which in turn drives activation of NF-kappa-B (Ea CK et al. 2006; Haas et al. 2009). The catalytic activity of LUBAC, composed of HOIL-1L, HOIP, and SHARPIN, specifically generates Met1-linked (also known as linear) polyUb chains (Kirisako T et al. 2006; Walczak H et al. 2012; Rittinger K & Ikeda F 2017; Fuseya Y & Iwai K 2021). UBE2L3 functions as E2-conjugating enzyme for LUBAC (Lewis MJ et al. 2015; Fu B et al. 2014). LUBAC was shown to catalyze Met1-linked ubiquitination of RIPK1 at K627 upon co-expression of Flag-RIPK1 with Myc-tagged components of LUBAC (HOIP, HOIL1, and SHARPIN) in human embryonic kidney 293T (HEK293T) cells (Tu H et al. 2021). Linear ubiquitination of mouse Ripk1 on K612 (K627 in human) inhibited TNF-α–induced apoptosis and necroptosis in mouse embryonic fibroblast (MEF) cells. Mutagenesis analysis further confirmed the importance of the K627 (K612 in mouse) ubiquitination site of RIPK1 in the TNFR1 signaling pathway (Li X et al. 2020). Further, LUBAC is known to ubiquitinate IKBKG (NEMO), a regulatory component of the IKK complex. LUBAC-mediated IKBKG ubiquitination enhanced IKBKG interaction with the TNFR1 signaling complex and stabilized this protein complex to promote activation of NF-kappa-B (Haas TL et al. 2009). Importantly, deletion of the LUBAC component SHARPIN in mice or mutation of HOIL-1 in humans, lead to hyperinflammatory phenotypes, indicating key roles of LUBAC and linear Ub chains in the response to infection and inflammation (Gerlach B et al. 2011; Ikeda F et al. 2011; Tokunaga F et al. 2011; Boisson B et al. 2012). The data suggest that LUBAC-mediated linear ubiquitylation of RIPK1 limits TNF-α–induced cell death.

This Reactome event describes LUBAC-mediated Met1-linked polyubiquitination (M1polyUb) of RIPK1 at K627 within the TNFR1 signaling complex.

Identifier: R-HSA-9693929
Species: Homo sapiens
Compartment: cytosol
Activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) controls tumor necrosis factor receptor (TNFR)- and pattern recognition receptors-mediated apoptosis, necroptosis and inflammatory pathways. RIPK1 activity is regulated post-translationally by ubiquitylation and phosphorylation events, as well as by caspase-8 (CASP8)-mediated cleavage. CASP8 facilitates the cleavage of human and mouse RIPK1 after residues D324 and D325, respectively and prevents caspase-8-dependent apoptosis and RIPK1:RIPK3-dependent necroptosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000; Newton K et al. 2019; Zhang X et al. 2019; Lalaoui N et al. 2020). The dominantly inherited mutations D324N, D324H, D324V and D324Y in RIPK1 prevent CASP8 from cleaving the mutated protein, thereby promoting activation of RIPK1 and leading to an autoinflammatory response in humans (Tao P et al. 2020; Lalaoui N et al. 2020).
Identifier: R-HSA-9687465
Species: Homo sapiens
Compartment: cytosol
Necroptosis complements apoptosis as a host defense pathway to stop virus infection. During infection in human cells, herpes simplex virus (HSV)-1 and HSV-2 modulate cell death pathways using the large subunit (R1) of viral ribonucleotide reductase (RIR1 or UL39) (Dufour F et al. 2011; Guo H et al. 2015; Yu X et al. 2016; Ali M et al.2019). The N-terminal region of RIR1 protein carrying the RIP homotypic interaction motif (RHIM)-like element is sufficient for RHIM-dependent interaction with receptor‐interacting protein kinase 1 (RIPK1) and receptor‐interacting protein kinase 3 (RIPK3) thus inhibiting the interaction between RIPK1 and RIPK3 (Guo H et al. 2015; Yu X et al. 2015). An intact RHIM is required for the interaction between RIPK1 and RIPK3 that occurs downstream of tumour necrosis factor receptor 1 (TNFR1) activation during the programmed cell death response known as necroptosis (Sun X et al. 2002). In addition, the large carboxyl-terminal region of HSV RIR1 protein mediates the binding to caspase 8 (CASP8) (Dufour F et al. 2011; Guo H et al. 2015). HSV RIR1 is thought to block necroptosis in infected human cells by interactions with RIPK1, RIPK3 and CASP8 (Guo H et al. 2015; Mocarski ES et al. 2015).

Set (1 results from a total of 9)

Identifier: R-HSA-6782771
Species: Homo sapiens
Compartment: cytosol

Complex (4 results from a total of 51)

Identifier: R-HSA-9793452
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9687467
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9693918
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6783081
Species: Homo sapiens
Compartment: cytosol
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