IKKα negatively regulates ASC-dependent inflammasome activation

Martin, Bradley N.; Wang, Chenhui; Willette-Brown, Jami; Herjan, Tomasz; Gulen, Muhammet F.; Zhou, Hao; Bulek, Katarzyna; Franchi, Luigi; Sato, Takashi; Alnemri, Emad S.; Narla, Goutham; Zhong, Xiaomei; Thomas, James A.; Klinman, Dennis M.; Fitzgerald, Katherine A.; Karin, Michael; Núñez, Gabriel; Dubyak, George R.; Hu, Yinling; Li, Xiaoxia

doi:10.1038/ncomms5977

Cited by 92 publications

(103 citation statements)

References 65 publications

(81 reference statements)

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“…Our findings suggest an association between the pyroptosome and the cell cycle machinery. Indeed, ASC localizes to the nucleus in resting cells and oligomerizes in the perinuclear region in response to activation (19,38). Furthermore, several reports linked ASC and caspase-1 to the cytoskeleton, including actin and microtubules (39 -42).…”

Section: Discussionmentioning

confidence: 99%

Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division

Stein

Kapplusch

Heymann

et al. 2016

Journal of Biological Chemistry

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Caspase-1 is a key player during the initiation of pro-inflammatory innate immune responses, activating pro-IL-1␤ in socalled inflammasomes. A subset of patients with recurrent febrile episodes and systemic inflammation of unknown origin harbor mutations in CASP1 encoding caspase-1. CASP1 variants result in reduced enzymatic activity of caspase-1 and impaired IL-1␤ secretion. The apparent paradox of reduced IL-1␤ secretion but systemic inflammation led to the hypothesis that CASP1 mutations may result in variable protein interaction clusters, thus activating alternative signaling pathways. To test this hypothesis, we established and characterized an in vitro system of transduced immortalized murine macrophages expressing either WT or enzymatically inactive (p.C284A) procaspase-1 fusion reporter proteins. Macrophages with variant p.C284A caspase-1 did not secrete IL-1␤ and exhibited reduced inflammatory cell death, referred to as pyroptosis. Caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) formed cytosolic macromolecular complexes (so-called pyroptosomes) that were significantly increased in number and size in cells carrying the p.C284A caspase-1 variant compared with WT caspase-1. Furthermore, enzymatically inactive caspase-1 interacted with ASC longer and with increased intensity compared with WT caspase-1. Applying live cell imaging, we documented for the first time that pyroptosomes containing enzymatically inactive variant p.C284A caspase-1 spread during cell division. In conclusion, variant p.C284A caspase-1 stabilizes pyroptosome formation, potentially enhancing inflammation by two IL-1␤-independent mechanisms: pyroptosomes convey an enhanced inflammatory stimulus through the recruitment of additional proteins (such as RIP2, receptor interacting protein kinase 2), which is further amplified through pyroptosome and cell division.Caspase-1 is a key player during innate immune responses. It aids to control pathogens and danger signals by triggering pyroptotic cell death. Together with caspase-11 and -12 in mice and caspase-4, -5, and -12 in humans, caspase-1 belongs to the family of inflammatory caspases, which are produced as inactive forms. After the detection of pathogens or cytoplasmic danger signals, inactive caspase-1 monomers recruit to multiprotein complexes referred to as inflammasomes (1-3). In such inflammasomes, inactive procaspases are autoprocessed into caspase activation and recruitment domains (CARDs), 2 the p10 and the p20 subunits (4). Two p10 and two p20 proteins subsequently form the active caspase-1 tetramer, which then cleaves and thereby activates IL-1␤ in the so-called canonical inflammasome pathway (5, 6). Furthermore, inflammatory caspases induce pro-inflammatory cell death, referred to as pyroptosis, which involves cell swelling, cell lysis, and the release of cytoplasmic contents (7,8). Pyroptosis depends on the activation of caspase-4, -5, or -11 and caspase-1 (9 -11). Caspase-1 or -11 cleaves gasdermin D, a gasdermin domain-containing protein, at amin...

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Section: Discussionmentioning

confidence: 99%

Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division

Stein

Kapplusch

Heymann

et al. 2016

Journal of Biological Chemistry

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“…POP3, an IFNγ-induced protein, directly binds to the PYD of AIM2 and blocks the recruitment of ASC 101 . d | IκB kinase-α (IKKα) retains ASC in the nucleus, thus controlling its availability 113 . POP1 binds to the PYD of ASC, thus preventing its recruitment to receptor PYDs and ASC polymerization 98 .…”

Section: Card-or Pyd-containing Regulatorsmentioning

confidence: 99%

Inflammasomes: mechanism of assembly, regulation and signalling

Brož

Dixit²

2016

Nat Rev Immunol

2,478

2,415

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Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.

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“…However, P improves recovery after TBI and in neurodegenerative disorders by positively affecting ROS formation and NFkappaB signaling [89][90][91]. Both pathological stressors of cell physiology and function are, in turn, identified as leading stimulators and activators of the inflammasome multiprotein complexes [92,93]. Under different neuropathological conditions, an array of inflammasome components are activated [30,94] and it is evident that post-ischemic DAMPs and their inflammasome counterparts are essential of neural protection [95].…”

Section: Gonadal Steroids and Inflammasome Regulationmentioning

confidence: 97%