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-alpha family members, is triggered by RIPK3 following activation by ZBP1 (PubMed:19590578, PubMed:22423968, PubMed:24012422, PubMed:24019532, PubMed:24557836, PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:24095729, PubMed:32200799, PubMed:27321907, 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).
