Cutting edge: the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms

J Immunol. 2014 Oct 1;193(7):3257-61. doi: 10.4049/jimmunol.1301886. Epub 2014 Sep 3.


Sensing of nucleic acids by TLRs is crucial in the host defense against viruses and bacteria. Unc-93 homolog B1 (UNC93B1) regulates the trafficking of nucleic acid-sensing TLRs from the endoplasmic reticulum to endolysosomes, where the TLRs encounter their respective ligands and become activated. In this article, we show that a carboxyl-terminal tyrosine-based sorting motif (YxxΦ) in UNC93B1 differentially regulates human nucleic acid-sensing TLRs in a receptor- and ligand-specific manner. Destruction of YxxΦ abolished TLR7, TLR8, and TLR9 activity toward nucleic acids in human B cells and monocytes, whereas TLR8 responses toward small molecules remained intact. YxxΦ in UNC93B1 influenced the subcellular localization of human UNC93B1 via both adapter protein complex (AP)1- and AP2-dependent trafficking pathways. However, loss of AP function was not causal for altered TLR responses, suggesting AP-independent functions of YxxΦ in UNC93B1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 1 / genetics
  • Adaptor Protein Complex 1 / immunology*
  • Adaptor Protein Complex 2 / genetics
  • Adaptor Protein Complex 2 / immunology*
  • Amino Acid Motifs
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / immunology*
  • Monocytes / cytology
  • Monocytes / immunology*
  • Protein Transport / genetics
  • Protein Transport / immunology
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology*


  • Adaptor Protein Complex 1
  • Adaptor Protein Complex 2
  • Membrane Transport Proteins
  • Toll-Like Receptors
  • UNC93B1 protein, human