Syk is involved in NLRP3 inflammasome-mediated caspase-1 activation through adaptor ASC phosphorylation and enhanced oligomerization

Abstract

NLRP3 is the most crucial member of the NLR family, as it detects the existence of pathogen invasion and self-derived molecules associated with cellular damage. Several studies have reported that excessive NLRP3 inflammasome-mediated caspase-1 activation is a key factor in the development of diseases. Recent studies have reported that Syk is involved in pathogen-induced NLRP3 inflammasome activation; however, the detailed mechanism linking Syk to NLRP3 inflammasome remains unclear. In this study, we showed that Syk mediates NLRP3 stimuli-induced processing of procaspase-1 and the consequent activation of caspase-1. Moreover, the kinase activity of Syk is required to potentiate caspase-1 activation in a reconstituted NLRP3 inflammasome system in HEK293T cells. The adaptor protein ASC bridges NLRP3 with the effector protein caspase-1. Herein, we find that Syk can associate directly with ASC and NLRP3 by its kinase domain but interact indirectly with procaspase-1. Syk can phosphorylate ASC at Y146 and Y187 residues, and the phosphorylation of both residues is critical to enhance ASC oligomerization and the recruitment of procaspase-1. Together, our results reveal a new molecular pathway through which Syk promotes NLRP3 inflammasome formation, resulting from the phosphorylation of ASC. Thus, the control of Syk activity might be effective to modulate NLRP3 inflammasome activation and treat NLRP3-related immune diseases.

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

“…Tyr146 in human ASC is equivalent to Tyr144 in mouse ASC; the phosphorylation of this residue is controlled by Syk and is critical for NLRP3-dependent ASC speck formation and IL-1β secretion78. However, it is not clear whether ASC is directly phosphorylated by Syk15.…”

“…To examine the role of Pyk2 and FAK in NLRP3- and AIM2-dependent secretion of IL-1β, we treated human monocyte-derived macrophages with the Pyk2/FAK dual inhibitor, PF-431396, the FAK-specific inhibitor, PF-573228, or the Syk inhibitor, R406 (positive control, as Syk was previously shown to be critical for ASC phosphorylation and IL-1β secretion78). We found that IL-1β secretion in response to ATP and poly(dA:dT) (which stimulate NLRP3 and AIM2 respectively) was significantly inhibited by all three inhibitors (Fig.…”

“…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.…”

Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation

“…These agonists activate the inflammasome through disparate pathways, such as membrane pore formation and lysosomal rupture, eventually converging on K + efflux and ASC phosphorylation and multimerization (14, 15). Reactive oxygen species (ROS) production has also been implicated to participate causally in the activation of NLRP3 (16–20).…”

Spleen Tyrosine Kinase as a Target Therapy for <b><i>Pseudomonas aeruginosa</i></b> Infection

“…This suggests that SYK may regulate innate immune responses to P. aeruginosa via its involvement in inflammasome activation. Other studies have shown that the inhibition of SYK activity might be effective to modulate NLRP3 activation [87].…”