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

Carlo Iavarone, Katrin Ramsauer, Andriy V. Kubarenko, Jason C. Debasitis, Igor Leykin, Alexander N.R. Weber, Owen M. Siggs, Bruce Beutler, Pu Zhang, Gillis Otten, Ugo D'Oro, Nicholas M. Valiante, M. Lamine Mbow, Alberto Visintin

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


TLR7 is the mammalian receptor for ssRNA and some nucleotide-like small molecules.We have generated a mouse by N-nitrose-N9- 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 TLR7rsq1. 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, TLR7rsq1 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 TLR7wt/wt splenocytes. Thus, TLR7rsq1 is a bona fide phenocopy of the TLR7 null mouse. Because TLR7rsq1 binds to ssRNA, our studies imply that the N-terminal portion of TLR7 triggers a yet to be identified event on TLR7. TLR7rsq1 mice might represent a valuable tool to help elucidate novel aspects of TLR7 biology.

Original languageEnglish
Pages (from-to)4213-4222
Number of pages10
JournalJournal of Immunology
Issue number7
Publication statusPublished - 1 Apr 2011
Externally publishedYes


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