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• W2023243246 abstract "Lysosomes have long been recognized as the “suicide bags” of cells.1 However, the exact mechanism by which the acidic endosomal-lysosomal cell compartment contributes to cell death is still under intense investigation. In terms of cell death modes, the classical dictum of unregulated necrosis vs. programmed caspase mediated-apoptosis has been recently extended by at least two necrotic pathways, namely caspase 1-dependent pyroptosis and RIP kinase-dependent necroptosis.2,3 Importantly, these new concepts suggest that necrosis is actually highly regulated and represents another form of programmed cell death. Since the actively regulated cell death pathways are executed primarily in the cytosol, lysosomal contents, such as lysosomal proteases, i.e., cathepsins, can only interfere with those pathways after the lysosomal enzymes have entered the cytosol in a still-ambiguous process that is often described and termed as lysosomal membrane permeabilization. Once in the cytosol, lysosomal cathepsins have been shown to proteolytically process multiple key molecules of the apoptotic machinery, thereby ensuring efficient execution of the apoptotic cell death program.4 Although cathepsin involvement in necrosis after lysosomal damage seems logical, there are no strong data concerning cathepsin substrates during necrosis. However, and to make matters more complex, cathepsin release from phagolysosomes of macrophages was implicated in Nlrp3 inflammasome activation and subsequent proteolytic maturation of interleukin 1β and its secretion as a physiological inflammatory cytokine.5In the June 15, 2013 issue of Cell Cycle, Lima and colleagues6 set out to dissect the role of cathepsins in these multiple processes in the immune system by treating murine macrophages with two types of lysosome disrupting agents: (1) Alum, which is widely used as adjuvant in immunizations, and (2) Leu-Leu-O-methylester (LLOMe), which needs to be polymerized by the acyl-transferase activity of cathepsin C in order to form the active membrane disrupting agent.7 By using these agents in a previous work employing a haploid screen and knockout cell lines, the authors found a cathepsin-controlled necrotic cell death that is biochemically clearly distinct from pyroptosis or necroptosis.8 They further demonstrated that cathepsins B and S control alum-mediated cell death, while LLOMe-mediated cell death is 100% controlled by cathepsin C, affirming the mechanism of LLOMe biotoxification. They also established that cathepsin C-dependent cell death was critical for induction of a strong adaptive immune response. In their recent study in Cell Cycle, the authors rigorously delineate this cathepsin-mediated cell death phenotype. They demonstrate that alum and LLOMe trigger distinct cellular pathways culminating in necrotic death. By addressing the lacking knowledge on cathepsin substrates during necrosis, the authors found that lysosome rupture and the associated release of lysosomal cathepsins causes a broad degradation of cytosolic proteins, including components of the Nlrp3 inflammasome. Though alum and LLOMe have been reported to activate the Nlrp3 inflammasome, the authors show that degradation of inflammasome components is consistent with a relative weak release of inflammasome-dependent cytokines and an Nlrp3/caspase-1-independent cell death.In summary, the authors provide evidence that lysosome-disrupting agents trigger a unique form of programmed necrotic cell death, which is distinct from established necrotic pathways. More broadly these data provide a mechanism by which, upon adjuvant application, the lysosome-mediated necrotic cell death itself may be decisive for polarizing the immune response to the Th2 type. Because of its significance for regulating inflammation, it remains to be discovered which terms and conditions of lysosomal membrane damage (cell type, degree of lysosomal permeabilization, etc.) favor an apoptotic or a necrotic type of cell death." @default.
• W2023243246 created "2016-06-24" @default.
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• W2023243246 date "2013-07-01" @default.
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• W2023243246 title "On the road to inflammation: Linking lysosome disruption, lysosomal protease release and necrotic death of immune cells" @default.
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• W2023243246 doi "https://doi.org/10.4161/cc.25316" @default.
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