Ripk3
entrez
56532
canonical
uniprot
Q9QZL0
canonical
ensembl
ENSMUSG00000022221
resolver
ensp
ENSMUSP00000022830
resolver
ensp
ENSMUSP00000126306
resolver
ensp
ENSMUSP00000137278
resolver
enst
ENSMUST00000022830
resolver
enst
ENSMUST00000168716
resolver
enst
ENSMUST00000178399
resolver
genesymbol
Ripk3
resolver
genesymbol_syn
Rip3
resolver
uniprot
E9PZP3
resolver
uniprot
G3X8V8
resolver
uniprot
Q3U3Z9
resolver
uniprot
Q8K2Y2
resolver
uniprot_entry
E9PZP3_MOUSE
resolver
uniprot_entry
RIPK3_MOUSE
resolver
uniprot_sec
G3X8V8
resolver
uniprot_sec
Q3U3Z9
resolver
uniprot_sec
Q8K2Y2
resolver
activity_regulation
ACTIVITY REGULATION: Activity is stimulated by ZBP1, which senses double-stranded Z-RNA structures (PubMed:32200799, PubMed:32296175). 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 (PubMed:24557836, PubMed:24813849, PubMed:24813850, PubMed:27321907, PubMed:27819681, PubMed:27819682, PubMed:32296175). Inhibited by type II inhibitor 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (PubMed:32184955). {ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27321907, ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:32184955, ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}.
uniprot
proteins
amino_acid_sequence
MSSVKLWPTGASAVPLVSREELKKLEFVGKGGFGVVFRAHHRTWNHDVAVKIVNSKKISWEVKAMVNLRNENVLLLLGVTEDLQWDFVSGQALVTRFMENGSLAGLLQPECPRPWPLLCRLLQEVVLGMCYLHSLNPPLLHRDLKPSNILLDPELHAKLADFGLSTFQGGSQSGSGSGSGSRDSGGTLAYLDPELLFDVNLKASKASDVYSFGILVWAVLAGREAELVDKTSLIRETVCDRQSRPPLTELPPGSPETPGLEKLKELMIHCWGSQSENRPSFQDCEPKTNEVYNLVKDKVDAAVSEVKHYLSQHRSSGRNLSAREPSQRGTEMDCPRETMVSKMLDRLHLEEPSGPVPGKCPERQAQDTSVGPATPARTSSDPVAGTPQIPHTLPFRGTTPGPVFTETPGPHPQRNQGDGRHGTPWYPWTPPNPMTGPPALVFNNCSEVQIGNYNSLVAPPRTTASSSAKYDQAQFGRGRGWQPFHK
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:27321907, PubMed:27746097, PubMed:27917412, PubMed:28607035, PubMed:32200799, PubMed:32296175). Necroptosis, a programmed cell death process in response to death-inducing TNF family members, is triggered by RIPK3 following activation by ZBP1 (PubMed:19590578, PubMed:22423968, PubMed:24012422, PubMed:24019532, PubMed:24095729, PubMed:24557836, PubMed:27321907, PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:32200799, PubMed:32296175). 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:24813849, PubMed:24813850, PubMed:27321907). 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 (PubMed:32200799, PubMed:32296175). Also regulates apoptosis: apoptosis depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity (PubMed:27321907). Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). In some cell types, also able to restrict viral replication by promoting cell death-independent responses (PubMed:30635240). In response to flavivirus 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 (PubMed:30635240). Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (PubMed:30635240). RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL (By similarity). These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity). {ECO:0000250|UniProtKB:Q9Y572, ECO:0000269|PubMed:19590578, ECO:0000269|PubMed:22423968, ECO:0000269|PubMed:24012422, ECO:0000269|PubMed:24019532, ECO:0000269|PubMed:24095729, ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27321907, ECO:0000269|PubMed:27746097, ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:27917412, ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:30635240, ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}.
uniprot
proteins
mass_dalton
53322
uniprot
proteins
mutagenesis
MUTAGEN 51; /note="K->A: Complete loss of induced necrosis."; MUTAGEN 111; /note="C->A: No effect."; /evidence="ECO:0000269|PubMed:24095729"; MUTAGEN 143; /note="D->N: Abolishes kinase activity and ability to mediate necroptosis. No autophosphorylation."; /evidence="ECO:0000269|PubMed:10490590, ECO:0000269|PubMed:24012422"; MUTAGEN 161; /note="D->N: Abolished protein kinase activity and ability to activate necroptosis. Knockin mice die during embryogenesis due to constitutive Ripk1- and Casp8-dependent apoptosis. Perinatal lethality observed in Ripk1 knockout mice is rescued in knockin mice carrying this mutation."; /evidence="ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:27819682"; MUTAGEN 230; /note="K->A: Slightly affects interaction with MLKL; when associated with A-236. Affects interaction with MLKL; when associated with A-232 and A-236."; /evidence="ECO:0000269|PubMed:24095729"; MUTAGEN 231; /note="T->A: Abolishes ability to mediate necroptosis."; /evidence="ECO:0000269|PubMed:23612963"; MUTAGEN 232; /note="S->A: Abolishes ability to mediate necroptosis. Affects interaction with MLKL; when associated with A-230 and A-236."; /evidence="ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:23612963, ECO:0000269|PubMed:24095729"; MUTAGEN 236; /note="E->A: Slightly affects interaction with MLKL; when associated with A-230. Affects interaction with MLKL; when associated with A-230 and A-232."; /evidence="ECO:0000269|PubMed:24095729"; MUTAGEN 448..451; /note="VQIG->AAAA: In RIPK3(RHIM); abolished interaction with ZBP1 and subsequent necroptosis. Perinatal lethality observed in Ripk1 knockout mice is rescued in knockin mice carrying this mutation."; /evidence="ECO:0000269|PubMed:18442983, ECO:0000269|PubMed:27819682
uniprot
proteins
post_translational_modification
PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). Autophosphorylated following interaction with ZBP1 (PubMed:27819681). Phosphorylation of Ser-204 plays a role in the necroptotic function of RIPK3 (By similarity). Autophosphorylates at Thr-231 and Ser-232 following activation by ZBP1: phosphorylation at these sites is a hallmark of necroptosis and is required for binding MLKL (PubMed:23612963, PubMed:27819682). Phosphorylation at Thr-187 is important for its kinase activity, interaction with PELI1 and for its ability to mediate TNF-induced necroptosis (By similarity). {ECO:0000250|UniProtKB:Q9Y572, ECO:0000269|PubMed:23612963, ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682}.; 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. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation. {ECO:0000250|UniProtKB:Q9Y572}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
10490590
uniprot
proteins
pubmed
14749364
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
18442983
uniprot
proteins
pubmed
19144319
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
19590578
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
22265413
uniprot
proteins
pubmed
22423968
uniprot
proteins
pubmed
23612963
uniprot
proteins
pubmed
24012422
uniprot
proteins
pubmed
24019532
uniprot
proteins
pubmed
24095729
uniprot
proteins
pubmed
24129315
uniprot
proteins
pubmed
24557836
uniprot
proteins
pubmed
24813849
uniprot
proteins
pubmed
24813850
uniprot
proteins
pubmed
27321907
uniprot
proteins
pubmed
27746097
uniprot
proteins
pubmed
27819681
uniprot
proteins
pubmed
27819682
uniprot
proteins
pubmed
27917412
uniprot
proteins
pubmed
28607035
uniprot
proteins
pubmed
28842570
uniprot
proteins
pubmed
29883609
uniprot
proteins
pubmed
30498077
uniprot
proteins
pubmed
30635240
uniprot
proteins
pubmed
31519887
uniprot
proteins
pubmed
31600504
uniprot
proteins
pubmed
32184955
uniprot
proteins
pubmed
32200799
uniprot
proteins
pubmed
32296175
uniprot
proteins
pubmed
34471287
uniprot
proteins
sequence_length
486
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}. Nucleus {ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}. Note=Mainly cytoplasmic (PubMed:32200799, PubMed:32296175). Present in the nucleus in response to influenza A virus (IAV) infection (PubMed:32200799). {ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}.
uniprot
proteins