Immunology Activated by Cleavage

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Toll-like receptors (TLRs) are pattern-recognition receptors that bind to pathogen-associated molecules to activate the innate immune response. TLRs contain an extracellular leucine-rich repeat (LRR) region, to which ligands bind; a transmembrane domain; and an intracellular Toll–interleukin-1 receptor (TIR) domain, to which adaptor molecules are recruited to trigger downstream signaling. TLRs are conserved among many species and are classified based on the types of activating ligands. Phylogenetically, avian TLR15 cannot be grouped with mammalian TLRs, and its ligand(s) and mechanism of action are unknown. de Zoete et al. found that TLR15 was localized to the plasma membrane of transfected cells and that it underwent glycosylation. TLR15 did not respond to any known TLR ligand tested, as assessed by nuclear factor B (NF-B) reporter assays; however, TLR15 responded to supernatant from yeast culture, a response that was prevented by heat treatment of the supernatant or by the presence of a protease inhibitor. TLR15, but not other TLRs, was activated by various proteases and fungal or bacterial culture supernatants, responses that were sensitive to protease inhibition. Western blotting analysis showed that TLR15 was proteolytically cleaved by those proteases that stimulated NF-B activation, whereas other TLRs were unaffected. Expression in transfected cells of a truncated TLR15 from which the extracellular domain (ECD) was removed resulted in constitutive activation of NF-B, a response that was insensitive to protease inhibitors. Together, these data suggest that avian TLR15 is cleaved by microbial proteases so that its ECD is removed and the receptor can activate NF-B in the absence of ligand.

M. R. de Zoete, L. I. Bouwman, A. M. Keestra, J. P. M. van Putten, Cleavage and activation of a Toll-like receptor by microbial proteases. Proc. Natl. Acad. Sci. U.S.A. 108, 4968–4973 (2011). [Abstract] [Full Text]

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