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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

Cai, Xinming and Xu, Yongyao and Cheung, Atwood and Tomlinson, Ronald and Alcazer-Roman, Abel and Murphy, Leon and Billich, Andreas and Feng, Yan and Zhang, Bailin and Klumpp, Martin and Rondeau, Jean-Michel and Fazal, Aleem and Wilson, Christopher and Myer, Vic and Joberty, Gerard and Bouwmeester, Antonius and Labow, Mark and Finan, Peter and Porter, Jeffrey and Ploegh, Hidde and Baird, Daniel and De Camilli, Pietro and Tallarico, John and Huang, Qian (2013) 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. Chemistry & Biology, 20. pp. 912-921.

Abstract

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.

Item Type: Article
Keywords: PIKfyve, TLR, IL-12/IL-23
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2804

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