Cai, Xinming, Xu, Yongyao, Cheung, Atwood, Tomlinson, Ronald, Alcazer-Roman, Abel, Murphy, Leon, Billich, Andreas, Feng, Yan, Zhang, Bailin, Klumpp, Martin, Rondeau, Jean-Michel, Fazal, Aleem, Wilson, Christopher, Myer, Vic, Joberty, Gerard, Bouwmeester, Antonius, Labow, Mark, Finan, Peter, Porter, Jeffrey, Ploegh, Hidde, Baird, Daniel, De Camilli, Pietro, 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