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J. Biol. Chem., Vol. 282, Issue 19, 13944-13953, May 11, 2007

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Nucleic Acids Exert a Sequence-independent Cooperative Effect on Sequence-dependent Activation of Toll-like Receptor 9^*

Jason Kindrachuk, Jean E. Potter, Robert Brownlie, Andrew D. Ficzycz, Philip J. Griebel, Neeloffer Mookherjee, George K. Mutwiri, Lorne A. Babiuk, and Scott Napper¹

From the Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3 and the Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Toll-like receptor 9 (TLR9) activates the innate immune system in response to microbial DNA or mimicking oligodeoxynucleotides. Although cell stimulation experiments demonstrate the preferential activation of TLR9 by CpG-containing nucleic acids, direct binding investigations have reached contradictory conclusions with respect to the ability of this receptor to bind nucleic acids in a sequence-specific manner. To address this apparent discrepancy, we report the purification of the soluble ectodomain of human TLR9 with characterization of its ligand binding properties. We observe that TLR9 has a high degree of specificity in its ability to bind nucleic acids that contain CpG dinucleotides as well as higher order motifs that mediate species-specific activation. However, TLR9 is also functionally influenced by nucleic acids in a sequence-independent fashion as both stimulatory and nonstimulatory nucleic acids sensitize TLR9 for in vitro ligand binding as well as in vivo activation. We propose a model in which receptor activation is achieved in a sequence-dependent manner, and sensitivity is modulated by the absolute concentration of nucleic acids in a sequence-independent fashion. This model bears resemblance to that recently proposed for Toll in that activation is a two-step process in which formation of a ligand-bound monomer precedes formation of the activated dimer. In each model receptor sensitivity is determined within the second step with the crucial distinction that Toll undergoes negative cooperativity, whereas TLR9 is sensitized through a positive cooperative effect.

Received for publication, August 23, 2006 , and in revised form, February 23, 2007.

^* This work was supported by funding from Qiagen Inc. and The Krembil Foundation and grants provided by the Natural Sciences and Engineering Research Council (to S. N. and L. A. B.), and Canadian Adaptation and Rural Development. Published with permission of the Director of Vaccine and Infectious Disease Organization as journal series number 451. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 306-966-1546; Fax: 306-966-7478; E-mail: scott.napper{at}usask.ca.

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