Article

UNC93B1 mediates differential trafficking of endosomal TLRs

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology , University of California, Berkeley , Berkeley , United States.
eLife Sciences (Impact Factor: 9.32). 02/2013; 2(2):e00291. DOI: 10.7554/eLife.00291
Source: PubMed

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

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    • "UNC93B1 also regulates excessive TLR7 signaling by recruiting TLR9 to counteract TLR7 (Fukui et al., 2009). In the case of TLR9 trafficking, interaction with the adapter protein-2 complex is also required (Lee et al., 2013; Chow et al., 2015). Protein associated with Toll-like receptor 4 is another resident protein of the endoplasmic reticulum that does not discriminate between intracellular and cell surface TLRs and plays a role in the exit of TLR1, TLR2, TLR4, TLR7, and TLR9 from the endoplasmic reticulum and their trafficking to plasma membrane and endosomes (Takahashi et al., 2007). "
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    • "All TLRs are synthesized in the ER, traffic to the Golgi, and are recruited to the cell surface or to intracellular compartments such as endosomes. Intracellular localization of TLRs is thought to be critical for ligand recognition as well as for preventing TLRs from coming into contact with self-nucleic acids, which could cause autoimmunity (26–29). The multi-pass transmembrane protein UNC93B1 controls the trafficking of intracellular TLRs from the ER to endosomes. "
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    • "Localization of TLR9 to the cell membrane has been reported in HEK293 as a consequence of stimulation with CpG DNA [5] on human peripheral blood mononuclear cells (PBMC) stimulated by LPS [45] and on mouse intestinal epithelial cells after exposure of cells to DNA from pathogenic Salmonella enterica [46]. Recently it has been reported that Unc93b1 is also required for the surface appearance of mouse TLR9 [47], however, we could not detect the surface localization of TLR9 on HEK293 cells. The reason for those differences may be that we investigated localization of the human and not mouse TLR9. "
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