RIPK3 phospho S227

Domain

The RIP homotypic interaction motif/RHIM mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3).

(Microbial infection) The RIP homotypic interaction motif/RHIM mediates interaction with the RHIM motif of the herpes simplex virus 1/HHV-1 protein RIR1/ICP6 to form heteromeric amyloid structures.

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). 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.

Post-translational modifications

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).

Sequence similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Tissue specificity

Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney.

Isoform 3

Expression is significantly increased in colon and lung cancers.

Cellular localization

• Cytoplasm
• Cytosol
• Nucleus
• Mainly cytoplasmic. Present in the nucleus in response to influenza A virus (IAV) infection.

Alternative names

• Receptor-interacting serine/threonine-protein kinase 3
• RIP-like protein kinase 3
• Receptor-interacting protein 3
• RIP-3
• RIP3
• RIPK3

Database links

• swissprot:Q9Y572

Target type

Proteins

Primary research area

Oncology

Molecular weight

56887Da