RIPK3
entrez
11035
canonical
uniprot
Q9Y572
canonical
ensembl
ENSG00000129465
resolver
ensembl
ENSG00000285379
resolver
ensp
ENSP00000216274
resolver
genesymbol
RIPK3
resolver
genesymbol_syn
RIP3
resolver
hgnc
HGNC:10021
resolver
uniprot
B4DJL9
resolver
uniprot
C4AM87
resolver
uniprot
Q5J795
resolver
uniprot
Q5J796
resolver
uniprot
Q6P5Y1
resolver
uniprot_entry
RIPK3_HUMAN
resolver
uniprot_sec
B4DJL9
resolver
uniprot_sec
C4AM87
resolver
uniprot_sec
Q5J795
resolver
uniprot_sec
Q5J796
resolver
uniprot_sec
Q6P5Y1
resolver
activity_regulation
ACTIVITY REGULATION: Activity is stimulated by ZBP1, which senses double-stranded Z-RNA structures (By similarity). RIPK3-dependent necroptosis is inhibited by RIPK1: RIPK1 prevents the ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (By similarity). {ECO:0000250|UniProtKB:Q9QZL0}.
uniprot
proteins
amino_acid_sequence
MSCVKLWPSGAPAPLVSIEELENQELVGKGGFGTVFRAQHRKWGYDVAVKIVNSKAISREVKAMASLDNEFVLRLEGVIEKVNWDQDPKPALVTKFMENGSLSGLLQSQCPRPWPLLCRLLKEVVLGMFYLHDQNPVLLHRDLKPSNVLLDPELHVKLADFGLSTFQGGSQSGTGSGEPGGTLGYLAPELFVNVNRKASTASDVYSFGILMWAVLAGREVELPTEPSLVYEAVCNRQNRPSLAELPQAGPETPGLEGLKELMQLCWSSEPKDRPSFQECLPKTDEVFQMVENNMNAAVSTVKDFLSQLRSSNRRFSIPESGQGGTEMDGFRRTIENQHSRNDVMVSEWLNKLNLEEPPSSVPKKCPSLTKRSRAQEEQVPQAWTAGTSSDSMAQPPQTPETSTFRNQMPSPTSTGTPSPGPRGNQGAERQGMNWSCRTPEPNPVTGRPLVNIYNCSGVQVGDNNYLTMQQTTALPTWGLAPSGKGRGLQHPPPVGSQEGPKDPEAWSRPQGWYNHSGK
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
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 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). {ECO:0000250|UniProtKB:Q9QZL0, ECO:0000269|PubMed:19498109, ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, ECO:0000269|PubMed:25316792, ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:32298652, ECO:0000269|PubMed:32657447}.; FUNCTION: (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. {ECO:0000269|PubMed:33348174}.
uniprot
proteins
mass_dalton
56887
uniprot
proteins
mutagenesis
MUTAGEN 50; /note="K->A: Abolishes kinase activity. Loss of PGAM5- and MLKL-binding. No effect on RIPK1-binding. Loss of interaction with PELI1 and PELI1-mediated ubiquitination. No loss of STUB1-mediated ubiquitination."; /evidence="ECO:0000269|PubMed:10339433, ECO:0000269|PubMed:10358032, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:29883609"; MUTAGEN 50; /note="K->D: Abolishes kinase activity."; /evidence="ECO:0000269|PubMed:10339433, ECO:0000269|PubMed:10358032, ECO:0000269|PubMed:22265414"; MUTAGEN 142; /note="D->N: Abolishes kinase activity and ability to mediate necroptosis."; /evidence="ECO:0000269|PubMed:22265413"; MUTAGEN 182; /note="T->A: Abolishes kinase activity. Loss of interaction with PELI1 and PELI1-mediated ubiquitination. No loss of interaction with STUB1 and STUB1-mediated ubiquitination. No loss of interaction with RIPK1. Loss of ability to mediate TNF-induced necroptosis. Loss of autophosphorylation at Ser-227."; /evidence="ECO:0000269|PubMed:29883609"; MUTAGEN 182; /note="T->S: No loss of interaction with PELI1 and PELI1-mediated ubiquitination. No loss of interaction with RIPK1 and MLKL."; /evidence="ECO:0000269|PubMed:29883609"; MUTAGEN 185; /note="Y->A,F: Loss of interaction with PELI1 and PELI1-mediated ubiquitination."; /evidence="ECO:0000269|PubMed:29883609"; MUTAGEN 227; /note="S->A: Abolishes ability to mediate necroptosis. Partial loss of kinase activity. No loss of PELI1-mediated degradation."; /evidence="ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:29883609"; MUTAGEN 227; /note="S->D: No loss of PELI1-mediated degradation."; /evidence="ECO:0000269|PubMed:29883609"; MUTAGEN 363; /note="K->R: Loss of PELI1-mediated ubiquitination. No loss of interaction with PELI1."; /evidence="ECO:0000269|PubMed:29883609"; MUTAGEN 458..461; /note="VQVG->AAAA: Abolished cleavage by S.flexneri OspD3."; /evidence="ECO:0000269|PubMed:32657447"; MUTAGEN 518; /note="K->R: Reduced necroptosis-associated ubiquitination and amplified necrosome formation and necroptotic cell death."; /evidence="ECO:0000269|PubMed:33369872
uniprot
proteins
post_translational_modification
PTM: (Microbial infection) Proteolytically cleaved by S.flexneri OspD3 within the RIP homotypic interaction motif (RHIM), leading to its degradation and inhibition of necroptosis. {ECO:0000269|PubMed:32657447}.; PTM: 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). {ECO:0000250|UniProtKB:Q9QZL0, ECO:0000269|PubMed:11734559, ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:29883609}.; PTM: 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). Deubiquitinated by USP22 (PubMed:33369872). {ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:33369872}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
10339433
uniprot
proteins
pubmed
10358032
uniprot
proteins
pubmed
11734559
uniprot
proteins
pubmed
12508121
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15896315
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
19498109
uniprot
proteins
pubmed
19524512
uniprot
proteins
pubmed
19524513
uniprot
proteins
pubmed
20354226
uniprot
proteins
pubmed
21887730
uniprot
proteins
pubmed
21931591
uniprot
proteins
pubmed
22265413
uniprot
proteins
pubmed
22265414
uniprot
proteins
pubmed
22421439
uniprot
proteins
pubmed
25316792
uniprot
proteins
pubmed
25674983
uniprot
proteins
pubmed
29681455
uniprot
proteins
pubmed
29883609
uniprot
proteins
pubmed
32298652
uniprot
proteins
pubmed
32657447
uniprot
proteins
pubmed
33348174
uniprot
proteins
pubmed
33369872
uniprot
proteins
sequence_length
518
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:22265413}. Nucleus {ECO:0000250|UniProtKB:Q9QZL0}. Note=Mainly cytoplasmic. Present in the nucleus in response to influenza A virus (IAV) infection. {ECO:0000250|UniProtKB:Q9QZL0}.
uniprot
proteins