Chemistry & Biology
Volume 20, Issue 7, 25 July 2013, Pages 912-921
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Article
PIKfyve, a Class III PI Kinase, Is the Target of the Small Molecular IL-12/IL-23 Inhibitor Apilimod and a Player in Toll-like Receptor Signaling

https://doi.org/10.1016/j.chembiol.2013.05.010Get rights and content
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Highlights

  • PIKfyve is the molecular and cellular target of IL-12/IL-23 antagonist apilimod

  • Apilimod is a potent and highly selective PIKfyve inhibitor

  • PIKfyve, a mammalian PI kinase, is required for TLR-induced production of IL-12/IL-23

Summary

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/IL-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/IL-23 with an unknown target and has been evaluated in clinical trials for patients with Crohn’s disease or rheumatoid arthritis. Using a chemical genetic approach, we show that it binds to PIKfyve and blocks its phosphotransferase activity, leading to selective inhibition of IL-12/IL-23p40. Pharmacological or genetic inactivation of PIKfyve is necessary and sufficient for suppression of IL-12/IL-23p40 expression. Thus, we have uncovered a phosphoinositide-mediated regulatory mechanism that controls TLR signaling.

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Present address: Sanofi-Aventis US, 270 Albany Street, Cambridge, MA 02139, USA

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Present address: Novartis Institutes for Biomedical Research, 104950BR Horsham, UK