The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

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.

A Plasmodium falciparum protein tyrosine phosphatase inhibitor identified from the ChEMBL‐NTD database blocks parasite growth

“…This process is mediated by kinases and phosphatases, to which a delicate balance is required for the successful completion of these cellular processes. Dysregulation of protein phosphorylation or alterations in phosphorylation patterns is a primary cause of many human diseases such as cancers, diabetes, autoimmune disorders, and neurological disorders [13,14,[18][19][20]. Kinases and phosphatases are fast emerging as novel drugable targets for many diseases, including diseases caused by various pathogens such as Plasmodium [13,14,[18][19][20][21]38].…”

“…Dysregulation of protein phosphorylation or alterations in phosphorylation patterns is a primary cause of many human diseases such as cancers, diabetes, autoimmune disorders, and neurological disorders [13,14,[18][19][20]. Kinases and phosphatases are fast emerging as novel drugable targets for many diseases, including diseases caused by various pathogens such as Plasmodium [13,14,[18][19][20][21]38]. We have carried out genome-wise phosphatome analysis of P. falciparum genome previously and identified four tyrosine phosphatases in the genome [10].…”

“…Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate diverse cellular processes such as cell motility, division, proliferation, and survival [13–16]. As the name suggests, PTPs regulate tyrosine phosphorylation of proteins and have a distinct active site signature motif, HCX5R [15,17].…”

“…Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate diverse cellular processes such as cell motility, division, proliferation, and survival [13][14][15][16]. As the name suggests, PTPs regulate tyrosine Abbreviations aa, amino acid; HDP, heme detoxification protein; MCS, multiple cloning sites; OMF, 3-O-methylfluorescein; OMFP, OMF phosphate; PBS, phosphate-buffered saline; Pf, Plasmodium falciparum; PfYVH1, Plasmodium falciparum dual-specificity protein phosphatase; PRL, phosphatase of regenerating liver; PTP, protein tyrosine phosphatase; RBC, red blood cell.…”

The receptor-type protein tyrosine phosphatase CD45 promotes onset and severity of IL-1β–mediated autoinflammatory osteomyelitis

“…SFKs are critical for initiation of signaling by a number of key leukocyte receptors, including those expressed by neutrophils ( 16 ). Moreover, there is a growing evidence about regulation of a major activator of IL-1β processing, NLRP3 inflammasome, by SFKs and downstream protein tyrosine kinases ( 17 , 18 , 19 , 20 , 21 , 22 , 23 ).…”