Kinases conquer the inflammasomes

Neumann, Konstantin; Ruland, Jürgen

doi:10.1038/ni.2763

Cited by 17 publications

(15 citation statements)

References 12 publications

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“…Phosphorylation of ASC Tyr146, which is required for the formation of ASC specks, is controlled by Syk and Jnk via an unknown pathway715. Our present data suggested that ASC forms the complex with p-FAK and p-Pyk2 (Fig.…”

Section: Resultssupporting

confidence: 50%

“…However, it is not clear whether ASC is directly phosphorylated by Syk15. Here, we utilized an online kinase prediction algorithm (PhosphoNET; http://www.phosphonet.ca/) to search for kinases that could potentially catalyze Tyr146 phosphorylation of ASC.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, other groups found that phosphorylation of ASC at Tyr146 is critical for its oligomerization in response to NLRP3 stimulation, and that the phosphorylation and oligomerization of ASC requires the kinase activity of Syk. However, studies examining whether ASC is a Syk substrate have yielded contradictory results7815. Moreover, the roles of other kinases involved in the direct phosphorylation of the NLRP3 inflammasome are largely unknown.…”

mentioning

confidence: 99%

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Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis

Chung

OuYang

Yuan

et al. 2016

Sci Rep

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The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation.

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Section: Resultssupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis

Chung

OuYang

Yuan

et al. 2016

Sci Rep

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“…More recently, Hare et al 27 demonstrated that Syk TK induces phosphorylation of Tyr-144 of ASC on activation of the NLRP3 and AIM2 inflammasomes, which is necessary for ASC oligomerization. However, it is still unknown whether Syk directly phosphorylates ASC or other TK(s) are involved 45 . In this study, we found that BTK, a TK structurally related to Syk, regulated activation of the NLRP3 inflammasome by interacting with NLRP3 and ASC.…”

Section: Discussionmentioning

confidence: 99%

Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury

et al. 2015

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Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. Inflammasomes mediate activation of caspase-1, which subsequently induces secretion of pro-inflammatory cytokines such as IL-1β and IL-18, as well as a form of cell death called pyroptosis. In this study, we report that Bruton's tyrosine kinase (BTK) is an essential component of the NLRP3 inflammasome, in which BTK physically interacts with ASC and NLRP3. Inhibition of BTK by pharmacological or genetic means severely impairs activation of the NLRP3 inflammasome. The FDA-approved BTK inhibitor ibrutinib (PCI-32765) efficiently suppresses infarct volume growth and neurological damage in a brain ischaemia/reperfusion model in mice. Ibrutinib inhibits maturation of IL-1β by suppressing caspase-1 activation in infiltrating macrophages and neutrophils in the infarcted area of ischaemic brain. Our study indicates that BTK is essential for NLRP3 inflammasome activation and could be a potent therapeutic target in ischaemic stroke.

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“…Spleen tyrosine kinase (Syk), a Src‐homology 2 (SH‐2) containing nonreceptor kinase, binds to integrins in a Src‐kinase dependent manner . At adhesion sites, Syk recruits and phosphorylates SH2‐domain containing nonreceptor tyrosine kinases such as focal adhesion kinase (FAK) or the homologous FAK‐related proline‐rich tyrosine kinase 2 (Pyk2) . FAK and Pyk2 also bind to actin‐binding proteins, like talin and paxillin, through the focal adhesion targeting (FAT) domain .…”

Section: Mechanotransduction‐associated Kinases In Inflammasome Signamentioning

confidence: 99%

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

Joshi

Morley

2019

Journal of Leukocyte Biology

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Many intracellular signals, such as host danger-associated molecules and bacterial toxins during infection, elicit inflammasome activation. However, the mechanical environment in tissues may also influence the sensitivity of various inflammasomes to activation. The cellular mechanical environment is determined by the extracellular tissue stiffness, or its inverse, tissue compliance. Tissue stiffness is sensed by the intracellular cytoskeleton through a process termed mechanotransduction. Thus, extracellular compliance and the intracellular cytoskeleton may regulate the sensitivity of inflammasome activation. Control of proinflammatory signaling by tissue compliance may contribute to the pathogenesis of diseases such as ventilator-induced lung injury during bacterial pneumonia and tissue fibrosis in inflammatory disorders. The responsible signaling cascades in inflammasome activation pathways and mechanotransduction crosstalk are not yet fully understood. This rather different immunomodulatory perspective will be reviewed and open questions discussed here. K E Y W O R D S cell adhesion, inflammasome, inflammation, integrins, mechanobiology, monocytes/macrophages

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Kinases conquer the inflammasomes

Cited by 17 publications

References 12 publications

Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis

Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis

Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

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