Abstract
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.
Highlights
Inflammasomes are multi-protein complexes responsible for the cleavage and subsequent release of several inflammatory cytokines, including IL-1β and IL-18 [1,2]
We summarize the effect of tyrosine phosphorylation on inflammasome components and highlight four specific tyrosine phosphatases that are involved in the regulation of inflammasomes at different stages of their activation
ASC activity is regulated via tyrosine phosphorylation, we found that PTPN2-mediated control of inflammasome activity was not mediated via direct interaction of PTPN2 with ASC, but that the effect of PTPN2 on ASC activity is mediated indirectly via modulation of Jun N-terminal kinase (JNK) activity [114] (Figure 1)
Summary
Inflammasomes are multi-protein complexes responsible for the cleavage and subsequent release of several inflammatory cytokines, including IL-1β and IL-18 [1,2]. Once ASC is recruited to inflammasome receptors, these receptor–ASC complexes serve as a nucleation point/scaffold for the formation of large ASC multimers called ASC-specks [1,2,3,4,5]. After their assembly, ASC-specks recruit the inactive pro-form of the inflammasome effector molecule caspase-1, which requires auto-catalysis for its activation [2]. Gasdermin D is a molecule of the gasdermin family that forms pores in the cell membrane to allow release of inflammasome-activated cytokines and initiates an inflammasome/caspase-1 dependent, highly pro-inflammatory form of cell death termed pyroptosis [6,7,8,9]
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