Σφακιανάκης Αλέξανδρος
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Τρίτη 15 Μαΐου 2018

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

Publication date: 15 May 2018
Source:Immunity, Volume 48, Issue 5
Author(s): Karin Pelka, Damien Bertheloot, Elisa Reimer, Kshiti Phulphagar, Susanne V. Schmidt, Anette Christ, Rainer Stahl, Nicki Watson, Kensuke Miyake, Nir Hacohen, Albert Haas, Melanie M. Brinkmann, Ann Marshak-Rothstein, Felix Meissner, Eicke Latz
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.

Graphical abstract

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Teaser

UNC93B1 is known as a trafficking chaperone for both endosomal TLRs and cell-surface TLR5, but how UNC93B1 transports its client TLRs to different compartments remains to be determined. Pelka and colleagues show that, in fact, UNC93B1 functions upstream of differential trafficking pathways and is crucial for stabilizing UNC93B1-dependent TLRs.


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