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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
MLKL Requires the Inositol Phosphate Code to Execute Necroptosis
Cole M Dovey1, Jonathan Diep1, Bradley P Clarke2
1Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract:
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.
Insights
Inositol phosphate (IP) kinases regulate cell death by controlling the mixed lineage kinase domain-like (MLKL) protein. This discovery reveals a metabolite
Area of Science:
- Cellular Biology
- Biochemistry
- Immunology
Background:
- Necroptosis is a critical lytic cell death pathway activated by injury and infection.
- The precise role of mixed lineage kinase domain-like (MLKL) in executing necroptosis remains incompletely understood.
Purpose of the Study:
- To investigate the sufficiency of MLKL in driving necroptosis.
- To identify genetic factors regulating MLKL-dependent necroptosis.
Main Methods:
- Genetic screening in human cells to identify mutants defective in MLKL-dependent necroptosis.
- Analysis of inositol phosphate (IP) kinase function in regulating necroptosis.
- Investigating MLKL oligomerization, membrane localization, and phosphorylation in IP kinase mutant cells.
Main Results:
- Mutations in inositol phosphate (IP) kinases (IPMK and ITPK1) were found to impair MLKL-dependent necroptosis.
- IP kinases are essential for necroptosis induced by various stimuli, including death receptor activation and viral infection.
- In IP kinase-deficient cells, MLKL failed to oligomerize and localize to membranes, despite correct phosphorylation by RIPK3.
- Necroptosis is dependent on IP-specific kinase activity, with a highly phosphorylated product displacing MLKL's auto-inhibitory region.
Conclusions:
- Metabolites, specifically inositol phosphates regulated by IP kinases, play a crucial role in controlling MLKL-mediated necroptosis.
- This study elucidates a key molecular mechanism by which regulated cell death is controlled through metabolic regulation of MLKL activation.
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