Showing papers by "Emad S. Alnemri published in 2007"
TL;DR: The results establish that macrophage pyroPTosis is mediated by a unique pyroptosome, distinct from the inflammasome, and stimulation of potassium efflux in THP-1 cells with potassium-depleting agents induces formation of the pyroaptosome.
Abstract: Pyroptosis is a caspase-1-dependent inflammatory form of cell death. The adapter protein ASC binds directly to caspase-1 and is critical for caspase-1 activation in response to a broad range of stimuli. To elucidate the mechanism of activation of caspase-1 by ASC and its exact role in macrophage pyroptosis, we performed time-lapse confocal bioimaging analysis on human THP-1 macrophages stably expressing an ASC-GFP fusion protein. We show that stimulation of these cells with several proinflammatory stimuli trigger the formation of a large supramolecular assembly of ASC, termed here pyroptosome. Only one distinct pyroptosome in each stimulated cell is formed, which rapidly recruits and activates caspase-1 resulting in pyroptosis and the release of the intracellular proinflammatory cytokines. The pyroptosome is largely composed of oligomerized ASC dimers. Dimerization of ASC is driven by subphysiological concentrations of potassium as in vitro incubation of purified recombinant ASC in the presence of subphysiological concentrations of potassium induces the assembly of a functional pyroptosome. Furthermore, stimulation of potassium efflux in THP-1 cells with potassium-depleting agents induces formation of the pyroptosome, while increasing potassium concentrations in the culture medium or pharmacological inhibition of this efflux inhibits its assembly. Our results establish that macrophage pyroptosis is mediated by a unique pyroptosome, distinct from the inflammasome.
892 citations
TL;DR: It is demonstrated that PSTPIP1 requires the familial Mediterranean fever protein pyrin to assemble the ASC pyroptosome, a molecular platform that recruits and activates caspase-1.
264 citations
TL;DR: The Parkinson's-disease-associated kinase PINK1 has been identified as an important regulator of the activity of the mitochondria-associated stress-protective protease HtrA2 in Parkinson's disease.
Abstract: Mitochondrial dysfunction is primarily responsible for neurodegeneration in Parkinson's disease. The Parkinson's-disease-associated kinase PINK1 has been identified as an important regulator of the activity of the mitochondria-associated stress-protective protease HtrA2.
26 citations