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PIKfyve, a class III PI-kinase, is the target of the small molecular IL12/23 inhibitor apilimod and a new player in toll-like receptor signaling #MMPMID23890009
Chem Biol 2013[Jul]; 20 (7): 912-21 PMID23890009show ga
Toll-Like Receptor (TLR) signaling is a key component of innate immunity. Aberrant TLR activation leads to immune disorders via dysregulation of cytokine production, such as IL-12/23. Herein we identify and characterize PIKfyve, a lipid kinase, as a critical player in TLR signaling using apilimod as an affinity tool. Apilimod is a potent small molecular inhibitor of IL-12/23 with an unknown target and has been evaluated in clinical trials for patients with Crohn?s disease or rheumatoid arthritis. Using a chemical genetics approach, we show that it binds to PIKfyve and blocks its phosphotransferase activity, leading to selective inhibition of IL-12/23p40. Pharmacological or genetic inactivation of PIKfyve is necessary and sufficient for suppression of IL-12/23p40 expression. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR signaling.