RIPK1-mediated regulated necrosis

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Homo sapiens
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Receptor-interacting kinase protein 1 (RIPK1) and RIPK3-dependent necrosis is called necroptosis or programmed necrosis. The kinase activities of RIPK1 and RIPK3 are essential for the necroptotic cell death in human, mouse cell lines and genetic mice models (Cho YS et al. 2009; He S et al. 2009, 2011; Zhang DW et al. 2009; McQuade T et al. 2013; Newton et al. 2014). The initiation of necroptosis can be stimulated by the same death ligands that activate apoptosis, such as tumor necrosis factor (TNF) alpha, Fas ligand (FasL), and TRAIL (TNF-related apoptosis-inducing ligand) or toll like receptors 3 and 4 ligands (Holler N et al. 2000; He S et al. 2009; Feoktistova M et al. 2011; Voigt S et al. 2014). In contrast to apoptosis, necroptosis represents a form of cell death that is optimally induced when caspases are inhibited (Holler N et al. 2000; Hopkins?Donaldson S et al. 2000; Sawai H 2014). Specific inhibitors of caspase-independent necrosis, necrostatins, have recently been identified (Degterev A et al. 2005, 2008). Necrostatins have been shown to inhibit the kinase activity of RIPK1 (Degterev A et al. 2008). Importantly, cell death of apoptotic morphology can be shifted to a necrotic phenotype when caspase 8 activity is compromised, otherwise active caspase 8 blocks necroptosis by the proteolytic cleavage of RIPK1 and RIPK3 (Kalai M et al. 2002; Degterev A et al. 2008; Lin Y et al. 1999; Feng S et al. 2007). When caspase activity is inhibited under certain pathophysiological conditions or by pharmacological agents, deubiquitinated RIPK1 is engaged in physical and functional interactions with its homolog RIPK3 leading to formation of necrosome, a necroptosis-inducing complex consisting of RIPK1 and RIPK3 (Sawai H 2013; Moquin DM et al. 2013; Kalai M et al. 2002; Cho YS et al. 2009, He S et al. 2009, Zhang DW et al. 2009). Within the necrosome RIPK1 and RIPK3 bind to each other through their RIP homotypic interaction motif (RHIM) domains. The RHIMs can facilitate RIPK1:RIPK3 oligomerization, allowing them to form amyloid?like fibrillar structures (Li J et al. 2012). RIPK3 in turn interacts with mixed lineage kinase domain?like protein (MLKL) (Sun L et al. 2012; Zhao J et al. 2012). The complex of RIPK1:RIPK3:MLKL is crucial for an execution phase of necroptosis which is strictly dependent on RIPK3-mediated phosphorylation of MLKL followed by MLKL oligomerization and translocation to membrane surfaces (Sun L et al. 2012; Wang H et al. 2014). Immunoblot analysis of cell fractions obtained by differential centrifugation of human colorectal adenocarcinoma (HT29) whole cell extracts suggests that upon necroptosis RIPK1:RIPK3:MLKL complexes shift to the plasma membrane and membranous organelles such as mitochondria, lysosome, endosome and ER (Wang H et al. 2014). These findings are supported by immunofluorescent imaging of subcellular distribution of necrosome components expressed in human cells (Wang H et al. 2014; Cai Z et al. 2014). The mechanisms of necroptosis regulation and execution downstream of MLKL remain elusive. MLKL has been proposed to induce necrosis execution in human cells (shown for HeLA and HT29 cell lines) by binding and activating phosphoglycerate mutase 5 (PGAM5) resulting in the induction of mitochondrial fission (Wang Z et al 2012). However, other studies showed that PGAM5-mediated mitochondrial fragmentation was dispensable for RIP?mediated necrosis in mouse cells (Murphy et al. 2013, Remijsen Q et al. 2014; Moujalled DM et al. 2014). Moreover, mitochondria-depleted 3T3 mouse embryo fibroblast cells were found to undergo necroptosis, suggesting that mitochondria axis may not be required for this process (Tait SW et al. 2013). Finally, RIPK3-activated MLKL has been also reported to translocate to lipid rafts of the plasma membrane where it facilitate cell death through membrane permeabilization (Cai Z et al. 2014; Dondelinger Y et al. 2014).

The Reactome module describes MLKL-mediated necroptotic events on the plasma membrane.

Literature References
PubMed ID Title Journal Year
24773756 Characterization of TNF-induced caspase-independent necroptosis

Sawai, H

Leuk. Res. 2014
24452471 Regulated necrosis: the expanding network of non-apoptotic cell death pathways

Vanden Berghe, T, Linkermann, A, Jouan-Lanhouet, S, Walczak, H, Vandenabeele, P

Nat. Rev. Mol. Cell Biol. 2014
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