The CARD plays a critical role in ASC foci formation and inflammasome signalling

Proell, Martina; Gerlic, Motti; Mace, Peter D.; Reed, John C.; Riedl, Stefan J.

doi:10.1042/bj20121198

Cited by 157 publications

(153 citation statements)

References 33 publications

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“…NLRC4 is unusual among the inflammasome-forming NLRs in that it can activate caspase-1 directly by CARD-CARD domain interactions as well as through association with the adaptor protein ASC (26,27). Our data suggest that changes in actin polymerization are an important effector mechanism for NLRC4-dependent ASC-independent antimicrobial effects induced by the cell, and we wondered whether this would also be true for ASC-dependent NLRC4 inflammasome activation by S. Typhimurium.…”

Section: Nlrc4 Modifies Actin Polymerization To Activate Inflammasomementioning

confidence: 86%

Actin polymerization as a key innate immune effector mechanism to control Salmonella infection

Man¹,

Ekpenyong

Tourlomousis³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Infectious diseases are responsible for one-third of all mortality worldwide. Innate immunity is critical for mounting host defenses that eliminate pathogens. Salmonella is a global food-borne pathogen that infects and replicates within macrophages. How inflammasomes—multimeric protein complexes that provide innate immune protection—function to restrict bacterial burden in macrophages remains unknown. We show that actin polymerization is critical for NLRC4 inflammasome activation in response to Salmonella infection. NLRC4 activation in Salmonella -infected cells prevents further uptake of bacteria by inducing cellular stiffness and antimicrobial responses, which prevent bacterial dissemination in the host. These results demonstrate a critical link between innate immunity and the actin cytoskeleton in the cellular defense against Salmonella infection.

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Section: Nlrc4 Modifies Actin Polymerization To Activate Inflammasomementioning

confidence: 86%

Actin polymerization as a key innate immune effector mechanism to control Salmonella infection

Man¹,

Ekpenyong

Tourlomousis³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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mentioning

confidence: 99%

“…For some NLRs, such as NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediates inflammasome assembly by interacting with capase-1 and the NLR (11,13,15). Complexes of NLRs and ASC form large structures in macrophages that can be detected as foci by microscopic techniques (17)(18)(19). In cases where inflammasome assembly is triggered in a T3SS-dependent manner upon infection of macrophages with pathogens, specific PAMPs identified to activate caspase-1 upon contaminating the cytosol include ectopically translocated flagellin, rod proteins, needle proteins, and translocated effector proteins (2,(11)(12)(13)15).…”

mentioning

confidence: 99%

Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence

et al. 2016

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Being the first line of defense against invading pathogens, the innate immune system has evolved to respond to general patterns of infection, termed pathogen-associated molecular patterns (PAMPs), via pattern recognition receptors (PRRs) (1, 2). Tolllike receptors (TLRs), acting as PRRs, detect distinct PAMPs from invading bacteria, such as flagellin (TLR5) and lipopolysaccharide (LPS; TLR4). Upon PAMP recognition, TLRs activate mitogenactivated protein kinase (MAPK) and nuclear factor-B (NF-B) pathways, which direct production of host-protective factors such as proinflammatory cytokines (3, 4). Bacterial pathogens produce virulence factors that inhibit PRR-directed innate immune responses in order to promote infection (5, 6). For example, numerous Gram-negative bacterial pathogens encode type III secretion systems (T3SSs) that are used to counteract host innate immune responses (7). During bacterium-host cell contact, T3SSs are activated and translocate effectors across the plasma membrane and into the eukaryotic cytosol. Translocated effectors inhibit innate immune responses and promote pathogenesis (7,8). In order to counteract infection by virulent pathogens, host cells can sense perturbations caused by T3SSs and/or effectors and produce heightened innate immune responses (9, 10).Disruptions induced by T3SSs and/or effectors in macrophages infected with bacterial pathogens commonly result in the activation of caspase-1 (11-14). Active caspase-1 promotes maturation and secretion of cytokines such as interleukin-1␤ (IL-1␤) and IL-18, which are produced as inactive precursors. Caspase-1 is also produced as a proenzyme, and its activation typically occurs in an inflammasome, a multioligomeric complex that serves as a molecular platform for the recruitment and auto-proteolytic cleavage of procaspase-1 (11-13, 15). Active caspase-1 also induces lysosome exocytosis and a form of inflammatory cell death, termed pyroptosis, which is characterized by osmotic swelling of the macrophage and subsequent rupture of the plasma membrane, resulting in the release of proinflammatory molecules (16). Several inflammasomes have been identified, and all but one (that formed by AIM2) contain proteins that are part of the nucleotidebinding domain leucine-rich repeat (NLR) family. These NLRs serve as cytosolic PRRs and are activated upon recognition of cytosolic PAMPs or danger signals (2,11,15). For some NLRs, such as NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediates inflammasome assembly by interacting with capase-1 and the NLR (11,13,15). Complexes of NLRs and ASC form large structures in macrophages that can be detected as foci by microscopic techniques (17)(18)(19). In cases where inflammasome assembly is

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“…The role of NLRP3 in caspase-1 activation and IL-1b secretion in response to these signals has been evaluated with the NLRP3 and ASC knockout mice, which both had defects for all tested stimuli (29,41,44,69), indicating that NLRP3 utilizes the ASC adapter. Moreover, NLRP3 has also been shown to bind ASC (3,21), and ASC foci are visible by immunofluorescence microscopy upon NLRP3 stimulation (71). Given the structurally diverse range of NLRP3 stimulants, it is not surprising that the molecular mechanism of NLRP3 activation remains unclear and will be discussed further in the following sections.…”

Section: The Inflammasomesmentioning

confidence: 99%

Regulation Where Autophagy Intersects the Inflammasome

Rodgers

Bowman

Liang

et al. 2014

Antioxidants & Redox Signaling

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Significance: The autophagy and inflammasome pathways are ancient innate immune mechanisms for controlling invading pathogens that are linked by mutual regulation. In addition to controlling the metabolic homeostasis of the cell through nutrient recycling, the ''self-eating'' process of autophagy is also responsible for the degradation of damaged organelles, cells, and pathogens to protect the integrity of the organism. As a cytosolic pathogen recognition receptor (PRR) complex, the inflammasome both induces and is induced by autophagy through direct interactions with autophagy proteins or through the effects of secondary molecules, such as mitochondrial reactive oxygen species and mitochondrial DNA. Recent Advances: While the molecular mechanisms of inflammasome activation and regulation are largely unknown, much of the current knowledge has been established through investigation of the role of autophagy in innate immunity. Likewise, regulatory proteins in the NOD-like receptor family, which includes inflammasome PRRs, are able to stimulate autophagy in response to the presence of a pathogen. Critical Issues: Many of the newly uncovered links between autophagy and inflammasomes have raised new questions about the mechanisms controlling inflammasome function, which are highlighted in this review. Future Directions: Our basic understanding of the mutual regulation of inflammasomes and autophagy will be essential for designing therapeutics for chronic inflammatory diseases, especially those for which autophagy and inflammasome genes have already been linked.

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The CARD plays a critical role in ASC foci formation and inflammasome signalling

Cited by 157 publications

References 33 publications

Actin polymerization as a key innate immune effector mechanism to control Salmonella infection

Actin polymerization as a key innate immune effector mechanism to control Salmonella infection

Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence

Regulation Where Autophagy Intersects the Inflammasome

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