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

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• 作者：Xinming Cai ; Yongyao Xu ; Atwood?K. Cheung ; Ronald?C. Tomlinson ; Abel Alc¨¢zar-Rom¨¢n ; Leon Murphy ; Andreas Billich ; Bailin Zhang ; Yan Feng ; Martin Klumpp ; Jean-Michel Rondeau ; Aleem?N. Fazal ; Christopher?J. Wilson ; Vic Myer ; Gerard Joberty ; Tewis Bouwmeester ; Mark?A. Labow ; Peter?M. Finan ; Jeffrey?A. Porter ; Hidde?L. Ploegh ; et al.
• 刊名：Chemistry & Biology
• 出版年：2013
• 出版时间：25 July, 2013
• 年：2013
• 卷：20
• 期：7
• 页码：912-921
• 全文大小：1630 K

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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.