RIPK3
The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, and contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce apoptosis and weakly activate the NF-kappaB transcription factor. [provided by RefSeq, Jul 2008]
Function
Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:29883609, PubMed:32657447).
Necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, is triggered by RIPK3 following activation by ZBP1 (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:29883609, PubMed:32298652).
Activated RIPK3 forms a necrosis-inducing complex and mediates phosphorylation of MLKL, promoting MLKL localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:25316792, PubMed:29883609).
In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity).
Also regulates apoptosis: apoptosis depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity (By similarity).
Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513).
In some cell types, also able to restrict viral replication by promoting cell death-independent responses (By similarity).
In response to Zika virus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with ZBP1, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate (By similarity).
Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity).
RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL (PubMed:19498109).
These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (PubMed:19498109).
(Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms heteromeric amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit RIPK3-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion.
Biological Process
Biological Process activation of protein kinase activityManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process amyloid fibril formationManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process apoptotic signaling pathwayManual Assertion Based On ExperimentTAS:ProtInc
Biological Process cellular response to hydrogen peroxideISS:ARUK-UCL
Biological Process defense response to virusISS:UniProtKB
Biological Process execution phase of necroptosisISS:UniProtKB
Biological Process I-kappaB kinase/NF-kappaB signalingIEA:Ensembl
Biological Process lymph node developmentISS:UniProtKB
Biological Process necroptotic processManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process necroptotic signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process positive regulation of intrinsic apoptotic signaling pathwayIEA:Ensembl
Biological Process positive regulation of ligase activityIEA:Ensembl
Biological Process positive regulation of necroptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of oxidoreductase activityIEA:Ensembl
Biological Process positive regulation of phosphatase activityManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process positive regulation of reactive oxygen species metabolic processIEA:Ensembl
Biological Process programmed necrotic cell deathISS:ARUK-UCL
Biological Process protein autophosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process protein modification processManual Assertion Based On ExperimentTAS:ProtInc
Biological Process reactive oxygen species metabolic processIEA:Ensembl
Biological Process regulation of activated T cell proliferationISS:UniProtKB
Biological Process regulation of activation-induced cell death of T cellsISS:UniProtKB
Biological Process regulation of adaptive immune responseISS:UniProtKB
Biological Process regulation of apoptotic processISS:UniProtKB
Biological Process regulation of CD8-positive, alpha-beta cytotoxic T cell extravasationISS:UniProtKB
Biological Process regulation of interferon-gamma productionISS:UniProtKB
Biological Process regulation of T cell mediated cytotoxicityISS:UniProtKB
Biological Process signal transductionManual Assertion Based On ExperimentIBA:GO_Central
Biological Process spleen developmentISS:UniProtKB
Biological Process T cell differentiation in thymusISS:UniProtKB
Biological Process T cell homeostasisISS:UniProtKB
Biological Process thymus developmentISS:UniProtKB
PTM
(Microbial infection) Proteolytically cleaved by S.flexneri OspD3 within the RIP homotypic interaction motif (RHIM), leading to its degradation and inhibition of necroptosis.
RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513).
Autophosphorylated following interaction with ZBP1 (By similarity).
Phosphorylation of Ser-199 plays a role in the necroptotic function of RIPK3 (PubMed:11734559, PubMed:19524512).
Autophosphorylates at Ser-227 following activation by ZBP1: phosphorylation at these sites is a hallmark of necroptosis and is required for binding MLKL (PubMed:22265413).
Phosphorylation at Thr-182 is important for its kinase activity, interaction with PELI1 and PELI1-mediated 'Lys-48'-linked polyubiquitination and for its ability to mediate TNF-induced necroptosis (PubMed:29883609).
Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591).
Polyubiquitinated with 'Lys-48'-linked chains by PELI1 leading to its subsequent proteasome-dependent degradation. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).
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