The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation

By T. Fernandes-Alnemri, Jianghong Wu, Je-Wook Yu, P. Datta, B. Miller, W. Jankowski, S. Rosenberg, Jianke Zhang, E. Alnemri. Cell Death and Differentiation, 2007

1,055 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology, Parasitology

View Paper: https://www.semanticscholar.org/paper/c316e2c99f1abb3b8903fe74e7e06442e54ad6bb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. J. Tschopp
2. T. Kanneganti
3. Guido Kroemer
4. Kate Schroder
5. G. Núñez
6. Shizuo Akira
7. L. Galluzzi
8. E. Latz

In Molecular Biology

1. T. Kanneganti
2. J. Tschopp
3. Guido Kroemer
4. Kate Schroder
5. L. Galluzzi
6. G. Núñez
7. Douglas R. Green
8. E. Latz

In Parasitology

1. L. Galluzzi
2. Guido Kroemer
3. Douglas R. Green
4. Eric H. Baehrecke
5. D. Rubinsztein
6. Beth Levine

Citations in the corpus

• Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 (2011, background): “Alternatively, caspase-1 can be activated by the so-called pyroptosome, a supramolecular assembly of ASC dimers.(153) In both cases, active caspase-1 catalyzes the proteolytic maturation and release of pyrogenic interleukin-1b (IL-1b) and IL-18.”
• Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome (2010, methodology): “To analyse the recruitment of ASC, we used macrophages stably expressing ASC fused to the fl uorescent protein CFP. 26 NLRP3 e ASC assembly results in the formation of fl uorescent specks, which can be visualised by fl uorescence microscopy.”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “In the case of some of these PRRs, such as NLRP1, NLRP3, AIM2, and pyrin, a bipartite adaptor protein, which is known as apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), facilitates the recruitment of pro-caspase-1 to the inflammasome complex [10].”
• NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases (2015, background): “…Univ Paris 06, UMR 8256, Biological Adaptation and Ageing - IBPS, F-75005 Paris, France b CNRS-UMR 8256, F-75005 Paris, France c Inserm U1164, F-75005 Paris, France d Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany a r t i c l e i n f o”
• The inflammasomes: guardians of the body. (2009, background): “(198) to propose an alternative hypothesis, namely that Pyrin, like NALP3, assembles an inflammasome with ASC and caspase-1.”
• Role of pyroptosis in inflammation and cancer (2022, background): “The pathways by which inflammasomes trigger pyroptosis are traditionally grouped into canonical pathways by caspase-1 activation or noncanonical pathways by caspase-11 or caspase-4/5 activation in mice or human beings, respectively [33, 34].”
• Human Monocytes Engage an Alternative Inflammasome Pathway. (2016, neutral): “These results were recapitulated in un-tagged BLaER1 monocytes using the chemical cross linker DSS, which only crosslinks ASC molecules that have been assembled into a pyroptosome due to spatial proximity (Fernandes-Alnemri et al., 2007).”
• Unified Polymerization Mechanism for the Assembly of ASC-dependent Inflammasomes (2014, background): “It has been shown previously that, upon stimulation, each cell forms one gigantic NLRP3 punctum adjacent to the nucleus (Fernandes-Alnemri et al., 2007).”
• Caspase-1 induced pyroptotic cell death (2011, background): “Because ASC is required for pyroptosis induction via NLRP3 and AIM2, the ASC focus has also been called the ‘pyroptosome’ (50); however, given recent results discussed below, this term should be”