UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5

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The proper trafficking and localization of Toll-like receptors (TLRs) are important for specific ligand recognition and efficient signal transduction. The TLRs sensing bacterial membrane components are expressed on the cell surface and recruit signaling adaptors to the plasma membrane upon stimulation. On the contrary, the nucleotide-sensing TLRs are mostly found inside cells and signal from the endolysosomes in an acidic pH-dependent manner. Trafficking of the nucleotide-sensing TLRs from the endoplasmic reticulum to the endolysosomes strictly depends on UNC93B1, and their signaling is completely abolished in the 3d mutant mice bearing the H412R mutation of UNC93B1. In contrast, UNC93B1 was considered to have no role for the cell surface-localized TLRs and signaling via TLR1, TLR2, TLR4, and TLR6 is normal in the 3d mice. Unexpectedly, we discovered that TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling. TLR5 physically interacts with UNC93B1, and the cells from the 3d or UNC93B1-deficient mice not only lack TLR5 at the plasma membrane but also fail to secret cytokines and to up-regulate costimulatory molecules upon flagellin stimulation, demonstrating the essential role of UNC93B1 in TLR5 signaling. Our study reveals that the role of UNC93B1 is not limited to the TLRs signaling from the endolysosomes and compels the further probing of the mechanisms underlying the UNC93B1-assisted differential targeting of TLRs.
Publisher
NATL ACAD SCIENCES
Issue Date
2014-05
Language
English
Article Type
Article
Keywords

DENDRITIC CELLS; NUCLEIC-ACID; BACTERIAL FLAGELLIN; TOXOPLASMA-GONDII; RECOGNITION; DNA; TOLL-LIKE-RECEPTOR-5; IMMUNITY; TLR9; EXPRESSION

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.111, no.19, pp.7072 - 7077

ISSN
0027-8424
DOI
10.1073/pnas.1322838111
URI
http://hdl.handle.net/10203/240791
Appears in Collection
MSE-Journal Papers(저널논문)
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