Kinase domain dimerization drives RIPK3-dependent necroptosis.
Saravanan Raju1, Daniel M Whalen2, Meron Mengistu3
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science Signaling
|August 23, 2018
Summary
Receptor-interacting protein kinase 3 (RIPK3) has a noncatalytic function crucial for necroptosis and apoptosis. Its kinase domain dimerization, independent of catalytic activity, regulates these cell death pathways.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Necroptosis is an inflammatory cell death pathway regulated by receptor-interacting protein kinase 3 (RIPK3) and RIPK1.
- A catalytically inactive RIPK3 mutant (D161N) induces embryonic lethality, suggesting non-catalytic roles for RIPK3.
Purpose of the Study:
- To investigate the noncatalytic functions of the RIPK3 kinase domain.
- To elucidate the mechanism of RIPK3-mediated apoptosis and necroptosis.
Main Methods:
- Analysis of RIPK3 D161N homozygous and heterozygous mice with and without RIPK1.
- Site-directed mutagenesis to disrupt RIPK3 kinase domain dimerization.
- Assessment of necroptosis and apoptosis induction.
Main Results:
- RIPK3 kinase domain homodimerization occurs via a surface similar to RAF kinases.
- Disruption of the dimer interface impairs RIPK3-dependent necroptosis.
- Kinase domain dimerization, through cis-autophosphorylation, activates RIPK3 and enhances its noncatalytic functions.
- Apoptosis induced by RIPK3 inhibitors depends on kinase dimerization.
Conclusions:
- The RIPK3 kinase domain possesses essential catalytically independent functions.
- RIPK3 kinase domain dimerization is a critical regulatory mechanism for both necroptosis and apoptosis.
- Targeting RIPK3 dimerization may offer therapeutic strategies for diseases involving aberrant cell death.
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