An outline of necrosome triggers
Open Access
- 6 April 2016
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cellular and Molecular Life Sciences
- Vol. 73 (11-12), 2137-2152
- https://doi.org/10.1007/s00018-016-2189-y
Abstract
Necroptosis was initially identified as a backup cell death program when apoptosis is blocked. However, it is now recognized as a cellular defense mechanism against infections and is presumed to be a detrimental factor in several pathologies driven by cell death. Necroptosis is a prototypic form of regulated necrosis that depends on activation of the necrosome, which is a protein complex in which receptor interacting protein kinase (RIPK) 3 is activated. The RIP homotypic interaction motif (RHIM) is the core domain that regulates activation of the necrosome. To date, three RHIM-containing proteins have been reported to activate the kinase activity of RIPK3 within the necrosome: RIPK1, Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), and DNA-dependent activator of interferon regulatory factors (DAI). Here, we review and discuss commonalities and differences of the increasing number of activators of the necrosome. Since the discovery that activation of mixed lineage kinase domain-like (MLKL) by RIPK3 kinase activity is crucial in necroptosis, interest has increased in monitoring and therapeutically targeting their activation. The availability of new phospho-specific antibodies, pharmacologic inhibitors, and transgenic models will allow us to further document the role of necroptosis in degenerative, inflammatory and infectious diseases.Keywords
This publication has 178 references indexed in Scilit:
- Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microgliaCell Death & Disease, 2013
- Resistance to hypoxia-induced necroptosis is conferred by glycolytic pyruvate scavenging of mitochondrial superoxide in colorectal cancer cellsCell Death & Disease, 2013
- TNF can activate RIPK3 and cause programmed necrosis in the absence of RIPK1Cell Death & Disease, 2013
- DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRACell Host & Microbe, 2012
- Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 KinaseCell, 2012
- TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II membersCell Death & Disease, 2011
- cIAPs Block Ripoptosome Formation, a RIP1/Caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP IsoformsMolecular Cell, 2011
- Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced InflammationCell, 2009
- Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-αCell, 2009
- Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF SignalingCurrent Biology, 2007