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Unc93b1 biases toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against rna-sensing

Academic Article
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Overview

authors

  • Fukui, R.
  • Saitoh, S.
  • Matsumoto, F.
  • Kozuka-Hata, H.
  • Oyama, M.
  • Tabeta, K.
  • Beutler, Bruce
  • Miyake, K.

publication date

  • June 2009

journal

  • Journal of Experimental Medicine  Journal

abstract

  • Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.

subject areas

  • Animals
  • Cell Line
  • DNA
  • Dendritic Cells
  • Humans
  • Lupus Erythematosus, Systemic
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mutation, Missense
  • RNA
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
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Identity

PubMed Central ID

  • PMC2715051

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20082316

PubMed ID

  • 19451267
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Additional Document Info

start page

  • 1339

end page

  • 1350

volume

  • 206

issue

  • 6

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