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J. Biol. Chem., Vol. 282, Issue 24, 17696-17705, June 15, 2007

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Effects of Single Nucleotide Polymorphisms on Toll-like Receptor 3 Activity and Expression in Cultured Cells^*

C. T. Ranjith-Kumar, William Miller, Jingchuan Sun^¶, Jin Xiong¹, Jon Santos, Ian Yarbrough, Roberta J. Lamb^||, Juliane Mills^||, Karen E. Duffy^||, Scott Hoose, Mark Cunningham^||, Andreas Holzenburg^¶, M. Lamine Mbow^||, Robert T. Sarisky^||, and C. Cheng Kao²

From the Departments of Biochemistry & Biophysics and Biology and the ^¶Microscopy and Imaging Center, Texas A&M University, College Station, Texas 77843 and ^||Discovery Research, Centocor Research and Development, Inc., Radnor, Pennsylvania 19087

Recognition of double-stranded RNA by Toll-like receptor 3 (TLR3) will increase the production of cytokines and chemokines through transcriptional activation by the NF-B protein. Over 136 single-nucleotide polymorphisms (SNPs) in TLR3 have been identified in the human population. Of these, four alter the sequence of the TLR3 protein. Molecular modeling suggests that two of the SNPs, N284I and L412F, could affect the packing of the leucine-rich repeating units in TLR3. Notably, L412F is reported to be present in 20% of the population and is higher in the asthmatic population. To examine whether the four SNPs affect TLR3 function, each were cloned and tested for their ability to activate the expression of TLR3-dependent reporter constructs. SNP N284I was nearly completely defective for activating reporter activity, and L412F was reduced in activity. These two SNPs did not obviously affect the level of TLR3 expression or their intracellular location in vesicles. However, N284I and L412F were underrepresented on the cell surface, as determined by flow cytometry analysis, and were not efficiently secreted into the culture medium when expressed as the soluble ectodomain. They were also reduced in their ability to act in a dominant negative fashion on the wild type TLR3 allele. These observations suggest that N284I and L412F affect the activities of TLR3 needed for proper signaling.

Received for publication, January 8, 2007 , and in revised form, April 9, 2007.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by the Welch Foundation.

² To whom correspondence should be addressed. Fax: 979-845-9274; E-mail: ckao{at}tamu.edu.

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