RIPK3
Description
The RIPK3 (receptor interacting serine/threonine kinase 3) is a protein-coding gene located on chromosome 14.
Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that is encoded by the RIPK3 gene in humans. The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. It 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 necroptosis by interaction with RIPK1 and MLKL in a protein complex termed the necrosome. Interactions between RIPK1 and RIPK3 also form a necrosome, which triggers apoptosis.
== Interactions == RIPK3 has been shown to interact with RIPK1 to form an amyloid spine The RIP Homotypic Interaction Motifs (RHIM) of RIPK3 allows it to form a necrosome with RIPK1. This interaction makes heterotypic β sheets, which bind together to form an alternating “ladder” of Serine from RIPK1 and Cysteine from RIPK3.
RIPK3 is a serine/threonine-protein kinase that triggers both necroptosis and apoptosis, two distinct forms of programmed cell death. Necroptosis, a response to death-inducing TNF-alpha family members, is initiated by RIPK3 when activated by ZBP1. RIPK3 forms a necrosis-inducing complex and phosphorylates MLKL, driving MLKL to the plasma membrane and executing programmed necrosis, characterized by calcium influx and plasma membrane disruption. In addition to TNF-induced necroptosis, necroptosis can also occur in the nucleus during orthomyxoviruses infections: following ZBP1 activation by double-stranded Z-RNA structures, nuclear RIPK3 phosphorylates and activates MLKL, leading to disruption of the nuclear envelope and leakage of cellular DNA into the cytosol. Apoptosis, on the other hand, relies on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity. RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. In certain cell types, RIPK3 can restrict viral replication by promoting cell death-independent responses. In response to Zika virus infection in neurons, RIPK3 collaborates with ZBP1 to initiate a death-independent transcriptional program that alters cellular metabolism. This program upregulates the enzyme ACOD1/IRG1 and produces itaconate, which inhibits succinate dehydrogenase and suppresses viral genome replication. RIPK3 binds and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL, potentially stimulating the tricarboxylic acid cycle and oxidative phosphorylation, leading to increased ROS production.
RIPK3 is also known as RIP3.
