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PNAS 108 (12): 4968-4973

Copyright © 2011 by the National Academy of Sciences.


Cleavage and activation of a Toll-like receptor by microbial proteases

Marcel R. de Zoete, Lieneke I. Bouwman, A. Marijke Keestra, and Jos P. M. van Putten1

Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL, Utrecht, The Netherlands

Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved February 8, 2011 (received for review December 3, 2010)

Abstract: Toll-like receptors (TLRs) are innate receptors that show high conservation throughout the animal kingdom. Most TLRs can be clustered into phylogenetic groups that respond to similar types of ligands. One exception is avian TLR15. This receptor does not categorize into one of the existing groups of TLRs and its ligand is still unknown. Here we report that TLR15 is a sensor for secreted virulence-associated fungal and bacterial proteases. Activation of TLR15 involves proteolytic cleavage of the receptor ectodomain and stimulation of NF-{kappa}B–dependent gene transcription. Receptor activation can be mimicked by the expression of a truncated TLR15 of which the entire ectodomain is removed, suggesting that receptor cleavage alleviates receptor inhibition by the leucine-rich repeat domain. Our results indicate TLR15 as a unique type of innate immune receptor that combines TLR characteristics with an activation mechanism typical for the evolutionary distinct protease-activated receptors.

Key Words: chicken • Pseudomonas • Toll-like receptor 9 • leucin-rich repeat

Author contributions: M.R.d.Z. and J.P.M.v.P. designed research; M.R.d.Z. and L.I.B. performed research; A.M.K. contributed new reagents/analytic tools; M.R.d.Z., L.I.B., A.M.K., and J.P.M.v.P. analyzed data; and M.R.d.Z. and J.P.M.v.P. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: j.vanputten{at}

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