Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes

Mambwe, Bezaleel; Neo, Kurt; Khameneh, Hanif Javanmard; Leong, K. W.; Colantuoni, Mariasilvia; Vacca, Maurizio; Muimo, Richmond; Mortellaro, Alessandra

doi:10.3389/fimmu.2019.01556

Cited by 27 publications

(19 citation statements)

References 37 publications

(45 reference statements)

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“…A more recent study by Mambwe et al showed that ASC phosphorylation at Tyr144 mediated its activation, while tyrosine phosphorylation at residues Tyr60 and Tyr137 inhibited ASC-speck formation. In addition to tyrosine kinase activity of Pyk2, such tyrosine phosphatase activity was also required for full ASC activation [73]. Taken together, these findings indicate that the tyrosine phosphorylation status at specific residues determines the ability of ASC to form specks and that depending on the involved tyrosine residue, phosphorylation can have opposite effects.…”

Section: The Adaptor Molecule Ascmentioning

confidence: 78%

The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

Spalinger

Schwarzfischer

Scharl

2020

IJMS

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Inflammasomes are multi-protein complexes that mediate the activation and secretion of the inflammatory cytokines IL-1β and IL-18. More than half a decade ago, it has been shown that the inflammasome adaptor molecule, ASC requires tyrosine phosphorylation to allow effective inflammasome assembly and sustained IL-1β/IL-18 release. This finding provided evidence that the tyrosine phosphorylation status of inflammasome components affects inflammasome assembly and that inflammasomes are subjected to regulation via kinases and phosphatases. In the subsequent years, it was reported that activation of the inflammasome receptor molecule, NLRP3, is modulated via tyrosine phosphorylation as well, and that NLRP3 de-phosphorylation at specific tyrosine residues was required for inflammasome assembly and sustained IL-1β/IL-18 release. These findings demonstrated the importance of tyrosine phosphorylation as a key modulator of inflammasome activity. Following these initial reports, additional work elucidated that the activity of several inflammasome components is dictated via their phosphorylation status. Particularly, the action of specific tyrosine kinases and phosphatases are of critical importance for the regulation of inflammasome assembly and activity. By summarizing the currently available literature on the interaction of tyrosine phosphatases with inflammasome components we here provide an overview how tyrosine phosphatases affect the activation status of inflammasomes.

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Section: The Adaptor Molecule Ascmentioning

confidence: 78%

The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

Spalinger

Schwarzfischer

Scharl

2020

IJMS

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“…Spleen tyrosine kinase (Syk) phosphorylates proline‐rich tyrosine kinase 2 (Pyk2) to induce subsequent phosphorylation of ASC at Tyr146 upon activation of both the NLRP3 and Absent in Melanoma 2 (AIM2) inflammasomes 68,69 . Dephosphorylation of ASC by protein tyrosine phosphatases (PTPases) at Tyr60 and Tyr137 is also essential for ASC speck formation and NLRP3 inflammasome activation, highlighting the dynamic nature of PTM‐mediated regulation 70 . It is unclear whether phosphorylation of Tyr146 or dephosphorylation of Tyr60 and Tyr137 are directly related to priming.…”

Section: Ptms Of Ascmentioning

confidence: 99%

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

McKee

Coll

2020

Journal of Leukocyte Biology

138

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The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is an immunological sensor that detects a wide range of microbial‐ and host‐derived signals. Inflammasome activation results in the release of the potent pro‐inflammatory cytokines IL‐1β and IL‐18 and triggers a form of inflammatory cell death known as pyroptosis. Excessive NLRP3 activity is associated with the pathogenesis of a wide range of inflammatory diseases, thus NLRP3 activation mechanisms are an area of intensive research. NLRP3 inflammasome activation is a tightly regulated process that requires both priming and activation signals. In particular, recent research has highlighted the highly complex nature of the priming step, which involves transcriptional and posttranslational mechanisms, and numerous protein binding partners. This review will describe the current understanding of NLRP3 priming and will discuss the potential opportunities for targeting this process therapeutically to treat NLRP3‐associated diseases.

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“…Phosphorylation-dephosphorylation events are also important for ASC oligomerization and its activity. Tyrosine kinase-mediated phosphorylation of human ASC at Y60, Y137, and Y146 (Y144 in murine ASC) is necessary for inflammasome assembly and subsequent inflammatory response [ 210 ]. Similarly, the dephosphorylation of ASC tyrosine residues is also essential in the activation of the NLRP3 inflammasome.…”

Section: Ascmentioning

confidence: 99%

“…Similarly, the dephosphorylation of ASC tyrosine residues is also essential in the activation of the NLRP3 inflammasome. For example, it has been reported that the compound phenylarsine oxide (PAO), a tyrosine phosphatase (PTPase) inhibitor, suppresses ASC oligomerization and speck formation in LPS-primed human THP-1 cells by targeting the self-association nucleation step [ 210 ].…”

Section: Ascmentioning

confidence: 99%

Structure, Activation and Regulation of NLRP3 and AIM2 Inflammasomes

Sharma

Alba

2021

IJMS

102

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The inflammasome is a three-component (sensor, adaptor, and effector) filamentous signaling platform that shields from multiple pathogenic infections by stimulating the proteolytical maturation of proinflammatory cytokines and pyroptotic cell death. The signaling process initiates with the detection of endogenous and/or external danger signals by specific sensors, followed by the nucleation and polymerization from sensor to downstream adaptor and then to the effector, caspase-1. Aberrant activation of inflammasomes promotes autoinflammatory diseases, cancer, neurodegeneration, and cardiometabolic disorders. Therefore, an equitable level of regulation is required to maintain the equilibrium between inflammasome activation and inhibition. Recent advancement in the structural and mechanistic understanding of inflammasome assembly potentiates the emergence of novel therapeutics against inflammasome-regulated diseases. In this review, we have comprehensively discussed the recent and updated insights into the structure of inflammasome components, their activation, interaction, mechanism of regulation, and finally, the formation of densely packed filamentous inflammasome complex that exists as micron-sized punctum in the cells and mediates the immune responses.

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Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes

Cited by 27 publications

References 37 publications

The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

Structure, Activation and Regulation of NLRP3 and AIM2 Inflammasomes

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