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: 8.52). 02/2013; 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:

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    • "First, the Berkeley team showed that translation of TLR7 mRNA into protein is inefficient, possibly due to TLR7 codon usage being highly suboptimal , and this results in levels of TLR7 that are often too low to be detected by Western blot (Lee et al., 2013). Further, the Berkeley work suggests that sending TLR7 to the plasma membrane might pose an unacceptable risk for the immune system by exposing the receptor to extracellular RNA (that was not produced by the virus). "
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