The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport

Immunity. 2018 May 15;48(5):911-922.e7. doi: 10.1016/j.immuni.2018.04.011.


Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. We discovered that UNC93B1 deficiency resulted in near-complete loss of TLR3 and TLR7 proteins in primary splenic mouse dendritic cells and macrophages, showing that UNC93B1 is critical for maintaining TLR expression. Notably, expression of an ER-retained UNC93B1 version was sufficient to stabilize TLRs and largely restore endosomal TLR trafficking and activity. These data are critical for an understanding of how UNC93B1 can regulate the function of a broad subset of TLRs.

Keywords: TLR; TLR trafficking; TLR13; TLR3; TLR7; TLR8; TLR9; Toll-like receptors; UNC93B; UNC93B1; nucleic acid sensing.

Publication types

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

MeSH terms

  • Animals
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / metabolism
  • Endosomes / immunology*
  • Endosomes / metabolism
  • HEK293 Cells
  • Humans
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / immunology*
  • Membrane Transport Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / immunology*
  • Molecular Chaperones / metabolism
  • Protein Stability
  • Protein Transport / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • THP-1 Cells
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology*
  • Toll-Like Receptors / metabolism


  • Membrane Transport Proteins
  • Molecular Chaperones
  • Toll-Like Receptors
  • UNC93B1 protein, mouse