UNC93B1 mediates differential trafficking of endosomal TLRs

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UNC93B1 mediates differential trafficking of endosomal TLRs

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DOI: http://dx.doi.org/10.7554/eLife.00291Published February 19, 2013 Cite as eLife 2013;2:e00291

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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Acknowledgements

We thank members of the Barton, Schekman, and Vance labs for helpful discussions and advice. We thank Hector Nolla for assistance with cell sorting at the Flow Cytometry Facility of the Cancer Research Laboratory at UC Berkeley. RS is supported as an Investigator of the Howard Hughes Medical Institute and as a Senior Fellow of the UC Berkeley Miller Institute.

Decision letter

Ruslan Medzhitov, Reviewing editor, Yale University, United States

eLife posts the editorial decision letter and author response on a selection of the published articles (subject to the approval of the authors). An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown. Reviewers have the opportunity to discuss the decision before the letter is sent (see review process). Similarly, the author response typically shows only responses to the major concerns raised by the reviewers.

Thank you for choosing to send your work entitled “Unc93b1 mediates differential trafficking of TLR7 and TLR9” for consideration at eLife. Your article has been evaluated by a Senior editor and 3 reviewers, one of whom is a member of our Board of Reviewing Editors.

The Reviewing editor and the other reviewers discussed their comments before we reached this decision, and the Reviewing editor has assembled the following comments based on the reviewers' reports.

This is an excellent study providing novel insights into the mechanisms of differential trafficking of TLR7 and TLR9 by the multipass transmembrane protein Unc93b1. The study will have general impact in immunology and cell biology. On the basis of enthusiastic comments by the Reviewing editor and two other reviewers, we will be happy to accept this paper for publication in eLife, provided that the authors address the minor issues raised by the reviewers:

1) A striking finding of this study is the differential use of the Unc93B/AP-2 trafficking pathway by TLR9 and TLR7. The authors suggest that TLR7 can direct itself to endosomes from the golgi through interactions with AP-4 subunits. Is this a common feature of the several TLRs that bind to Unc93B? If yeast 2-hybrid analyses are performed with other endosomal TLRs, are there other examples of TLR-AP4 interactions, or is TLR7 unique?

2) The authors make the intriguing suggestion that Unc93B binds to a single TLR at a time. This model predicts that at least five different complexes of Unc93B exist in cells (Unc-TLR9 complexes, Unc-TLR7 complexes, etc). If this is true, then immunoprecipitation assays with TLR7 should not be able to co-purify TLR9, while Unc93B pulldowns should isolate both TLR7 and TLR9. The authors are encouraged to perform these assays.

3) In Figure 7, the schematic figure indicates the role of AP-1 in transfer of TLR9 from Golgi to the plasma membrane. However, we could not find data for this in the study. Can the authors clarify this?

DOI: http://dx.doi.org/10.7554/eLife.00291.012

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