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Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012 Jul 20;150(2):339-50. PubMed.
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VIB, Ghent University
Amyloid aggregation in programmed necrosis or necroptosis
Our lab was one of the first describing necrotic cell death as a programmed form of cell death implicated in many inflammatory and degenerative pathologies (Vandenabeele et al., 2010). Until recently, the prototype cell death mechanism has been thought to be apoptosis, which involves activation of a cascade of caspases and the consecutive cleavage of proteins. Nowadays, regulated or programmed necrosis, also called necroptosis, is viewed as another major type of cell death. Necroptosis is mainly driven by the combined action of receptor interacting protein kinase 1 (RIPK1) and RIPK3 kinases (Declercq et al., 2009). Targeting these RIP kinases by small-molecule inhibitors (necrostatins) (Degterev et al., 2008) has been proven as a powerful tool to block necrotic cell death both in vitro and in vivo.
Many stimuli can elicit necrotic cell death including pathogens, TNF family members, pathogen associated molecular patterns (PAMPs), damage associated molecular patterns (DAMPs), and also some chemotherapeutics (Vanlangenakker et al., 2012). All these have been shown to activate or sensitize the formation of RIPK-containing complexes (called stressosome, ripoptosome, necrosome), which are implicated in the initiation of inflammatory and/or cell death signaling either by apoptosis or necroptosis (Vandenabeele et al., 2010). Which type of cell death ensues depends on the composition of these RIPK-containing complexes; for example, low levels of caspase 8 and the presence of RIPK3 kinase favor the necroptosis outcome.
This recent paper by Li et al. represents a collaborative effort by the cell death expert group of Francis Chan (University of Massachusetts Medical School) and the structural biology expert group of Hao Wu (Weill Cornell Medical College and Harvard Medical School). They demonstrate elegantly how the cell death-inducing complex forms a large β amyloid-like structure of heterodimeric RIP1 and RIP3 in a 1:1 ratio. This filamentous fibril formation is initiated by necroptosis-inducing agents and depends on a core around the hydrophobic RHIM domain motif which allows heterotypic interaction between both kinases. The kinase activity of both RIP1 and RIP3 are required to induce this extremely stable amyloid-like structure, probably by causing an auto- and transphosphorylation-dependent exposure of the hydrophobic core of the RHIM domain. This aggregation forms seeds that can induce further polymerization, much like prions do. These RIP kinase-driven β amyloid-like structures may form a platform on which cell-death signaling molecules are recruited and propagated. Formation of higher-order scaffolds by death domain folds (Kersse et al., 2011), and now by RHIM domains, is an emerging theme in inflammation and cell-death signaling, and in cellular stress in general. It is still not clear what really initiates Alzheimer’s disease (Benilova et al., 2012); however, it is clear that the amyloid state of proteins may initiate or propagate toxic signaling pathways (Eisenberg and Jucker, 2012). Given that the core protein complex of necroptosis or programmed necrosis forms amyloid-like structures very similar to those observed in Alzheimer’s disease, and that amyloid structures may induce co-aggregation of other amyloidogenic proteins (Eisenberg and Jucker, 2012), it is conceivable that necroptosis processes may contribute to Alzheimer’s disease (AD) pathogenesis. The good news is that targeting necroptosis is recently possible thanks to RIPK1 kinase inhibitors such as necrostatins (Degterev et al., 2008). The big search for specific RIPK1 and RIPK3 kinase inhibitors has been started now, and if (though a big "if"!) necrotic cell death processes are implicated in AD pathogenesis, the use of these kinase inhibitors may retard the onset of the disease by interfering with the formation of RIPK1 and RIPK3 amyloid filamentous fibrils.
References:
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Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival. Cell. 2009 Jul 23;138(2):229-32. PubMed.
Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008 May;4(5):313-21. PubMed.
Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell. 2012 Mar 16;148(6):1188-203. PubMed.
Kersse K, Verspurten J, Vanden Berghe T, Vandenabeele P. The death-fold superfamily of homotypic interaction motifs. Trends Biochem Sci. 2011 Oct;36(10):541-52. PubMed.
Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012 Jul 20;150(2):339-50. PubMed.
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14. Epub 2010 Sep 8 PubMed.
Vanlangenakker N, Vanden Berghe T, Vandenabeele P. Many stimuli pull the necrotic trigger, an overview. Cell Death Differ. 2012 Jan;19(1):75-86. PubMed.
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