Phospho-MLKL (Ser358)

This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis. High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]

Full Name

Mixed Lineage Kinase Domain Like Pseudokinase

Function

Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671).

Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671).

Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671).

In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.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).

Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610).

Biological Process

Cell surface receptor signaling pathway Source: InterPro
Defense response to virus Source: UniProtKB
Execution phase of necroptosis Source: UniProtKB
Necroptotic process Source: UniProtKB
Necroptotic signaling pathway Source: UniProtKB
Protein homotrimerization Source: UniProtKB

Cellular Location

Cytoplasm
Nucleus
Plasma membrane
Cell membrane
Note: Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction (PubMed:24316671). Localizes to the nucleus in response to orthomyxoviruses infection (By similarity).

PTM

Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis (PubMed:22265413). It also induces homotrimerization and localization to the plasma membrane (PubMed:22265413).