UNC93B1 mediates differential trafficking of endosomal TLRs

Elife. 2013 Feb 19;2:e00291. doi: 10.7554/eLife.00291.

Abstract

UNC93B1, a multipass transmembrane protein required for TLR3, TLR7, TLR9, TLR11, TLR12, and TLR13 function, controls trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes. The mechanisms by which UNC93B1 mediates these regulatory effects remain unclear. Here, we demonstrate that UNC93B1 enters the secretory pathway and directly controls the packaging of TLRs into COPII vesicles that bud from the ER. Unlike other COPII loading factors, UNC93B1 remains associated with the TLRs through post-Golgi sorting steps. Unexpectedly, these steps are different among endosomal TLRs. TLR9 requires UNC93B1-mediated recruitment of adaptor protein complex 2 (AP-2) for delivery to endolysosomes while TLR7, TLR11, TLR12, and TLR13 utilize alternative trafficking pathways. Thus, our study describes a mechanism for differential sorting of endosomal TLRs by UNC93B1, which may explain the distinct roles played by these receptors in certain autoimmune diseases.DOI:http://dx.doi.org/10.7554/eLife.00291.001.

Keywords: AP-2; Mouse; Toll-like receptors; UNC93B1; trafficking.

Publication types

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

MeSH terms

  • Adaptor Protein Complex 2 / metabolism
  • Animals
  • COP-Coated Vesicles / metabolism
  • COS Cells
  • Chlorocebus aethiops
  • Endoplasmic Reticulum / metabolism
  • Endosomes / metabolism*
  • Golgi Apparatus / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Protein Transport
  • RNA Interference
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism*
  • Transfection

Substances

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