Evasion of inflammasome activation by microbial pathogens

Ulland, Tyler K.; Ferguson, Polly J.; Sutterwala, Fayyaz S.

doi:10.1172/jci75254

Cited by 57 publications

(52 citation statements)

References 116 publications

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“…This indicates that activation of the apoptotic caspase-3 in the absence of inflammatory caspases could serve to induce secondary necrosis through cleavage of DFNA5. Therefore, in addition to it being involved in secondary necrosis, the DFNA5 pathway might also serve as a backup pathway in the events of inflammasome inhibition by pathogen-mediated inflammasome-suppression strategies4445. For example, cowpox virus and orthopoxviruses encode serpins such as CrmA that inhibit the activity of caspase-1, whereas myxoma virus and Shope fibroma virus encode pyrin-only proteins that inhibit inflammasome assembly46474849.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

et al. 2017

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Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis.

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Section: Discussionmentioning

confidence: 99%

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

et al. 2017

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“…The inflammasome is important for defense against many infections including intracellular bacterial pathogens (Sansonetti et al , 2000; Mariathasan et al , 2005; Lara-Tejero et al , 2006; Broz et al , 2010), as well as fungal and viral pathogens (Rathinam et al , 2010; van de Veerdonk and Joosten, 2015). To counter this host defense, many pathogens have evolved mechanisms to avoid or even actively inhibit inflammasome activation (Taxman et al , 2010; Lamkanfi and Dixit, 2011; Ulland et al , 2015). Despite substantial progress on the molecular mechanisms of inflammasome activation, little is known about how host protection is mediated and what the role of specific innate immune cell populations is during acute infection in vivo.…”

Section: Introductionmentioning

confidence: 99%

Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish

Vincent

Freisinger

Lam

et al. 2015

Cellular Microbiology

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Summary The inflammasome is an innate immune complex whose rapid inflammatory outputs play a critical role in controlling infection, however the host cells that mediate inflammasome responses in vivo are not well defined. Using zebrafish larvae, we examined the cellular immune responses to inflammasome activation during infection. We compared the host responses to two Listeria monocytogenes strains: wild type and Lm-pyro, a strain engineered to activate the inflammasome via ectopic expression of flagellin. Infection with Lm-pyro led to activation of the inflammasome, macrophage pyroptosis, and ultimately attenuation of virulence. Depletion of caspase A, the zebrafish caspase-1 homolog, restored Lm-pyro virulence. Inflammasome activation specifically recruited macrophages to infection sites, whereas neutrophils were equally recruited to WT and Lm-pyro infections. Similar to caspase A depletion, macrophage deficiency rescued Lm-pyro virulence to wild type levels, while defective neutrophils had no specific effect. Neutrophils were however important for general clearance of L. monocytogenes, as both wild type and Lm-pyro were more virulent in larvae with defective neutrophils. This study characterizes a novel model for inflammasome studies in an intact host, establishes the importance of macrophages during inflammasome responses, and adds importance to the role of neutrophils in controlling L. monocytogenes infections.

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“…24 Shigella flexneri causes NLRP3-dependent necrosis and HMGB1 release in macrophages associated with further tissue damage. 25 Yersinia pestis infection can also induce macrophage necrosis, which is dispensable for innate host resistance but contributes to enhanced cytotoxicity. 26 However, the role of NLRP3-dependent necrosis in Y. pestis pathogenesis remains further investigation.…”

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confidence: 99%

The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3

Wei¹,

Wang²,

et al. 2016

Cell Death Dis

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Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein. Specially, YopM associates with NLRP3, and its CLD ligase motif mediates the activating K63-linked ubiquitylation of NLRP3; as a result, YopM modulates NLRP3-mediated cell necrosis. Mutation of YopM E3 ligase motif dramatically reduces the ability of Y. pestis to induce HMGB1 release and cell necrosis, which ultimately contributes to bacterial virulence. In conclusion, this study has identified a previously unrecognized role for YopM E3 ligase activity in the regulation of host cell necrosis and plague pathogenesis.

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Evasion of inflammasome activation by microbial pathogens

Cited by 57 publications

References 116 publications

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish

The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3

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