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A point mutation in the amino terminus of TLR7 abolishes signaling without affecting ligand binding

Academic Article
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Overview

related to degree

  • Siggs, Owen Marc, Ph.D. in Biology, Scripps Research , Joint graduate program with Oxford University 2007 - 2012

authors

  • Iavarone, C.
  • Ramsauer, K.
  • Kubarenko, A. V.
  • Debasitis, J. C.
  • Leykin, I.
  • Weber, A. N. R.
  • Siggs, Owen Marc
  • Beutler, Bruce
  • Zhang, P.
  • Otten, G.
  • D'Oro, U.
  • Valiante, N. M.
  • Mbow, M. L.
  • Visintin, A.

publication date

  • April 2011

journal

  • Journal of Immunology  Journal

abstract

  • TLR7 is the mammalian receptor for ssRNA and some nucleotide-like small molecules. We have generated a mouse by N-nitrose-N'-ethyl urea mutagenesis in which threonine 68 of TLR7 was substituted with isoleucine. Cells bearing this mutant TLR7 lost the sensitivity to the small-molecule TLR7 agonist resiquimod, hence the name TLR7(rsq1). In this work, we report the characterization of this mutant protein. Similar to the wild-type counterpart, TLR7(rsq1) localizes to the endoplasmic reticulum and is expressed at normal levels in both primary cells and reconstituted 293T cells. In addition to small-molecule TLR7 agonists, TLR7(rsq1) fails to be activated by ssRNA. Whole-transcriptome analysis demonstrates that TLR7 is the exclusive and indispensable receptor for both classes of ligands, consistent with the fact that both ligands induce highly similar transcriptional signatures in TLR7(wt/wt) splenocytes. Thus, TLR7(rsq1) is a bona fide phenocopy of the TLR7 null mouse. Because TLR7(rsq1) binds to ssRNA, our studies imply that the N-terminal portion of TLR7 triggers a yet to be identified event on TLR7. TLR7(rsq1) mice might represent a valuable tool to help elucidate novel aspects of TLR7 biology.

subject areas

  • Animals
  • Cell Line
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Imidazoles
  • Ligands
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Point Mutation
  • Protein Binding
  • Signal Transduction
  • Toll-Like Receptor 7
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.1003585

PubMed ID

  • 21383246
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Additional Document Info

start page

  • 4213

end page

  • 4222

volume

  • 186

issue

  • 7

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