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J. Cell Biol. 177 (2): 265-275

Copyright © 2007 by the Rockefeller University Press.


Article

The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling

Melanie M. Brinkmann1, Eric Spooner1, Kasper Hoebe2, Bruce Beutler2, Hidde L. Ploegh1, , and You-Me Kim1

1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142
2 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Correspondence to Hidde L. Ploegh: ploegh{at}wi.mit.edu; or You-Me Kim: ykim{at}wi.mit.edu

Abstract: Toll-like receptors (TLRs) sense the presence of microbial and viral pathogens by signal transduction mechanisms that remain to be fully elucidated. A single point mutation (H412R) in the polytopic endoplasmic reticulum (ER)–resident membrane protein UNC93B abolishes signaling via TLR3, 7, and 9. We show that UNC93B specifically interacts with TLR3, 7, 9, and 13, whereas introduction of the point mutation H412R in UNC93B abolishes their interactions. We establish the physical interaction of the intracellular TLRs with UNC93B in splenocytes and bone marrow–derived dendritic cells. Further, by expressing chimeric TLRs, we show that TLR3 and 9 bind to UNC93B via their transmembrane domains. We propose that a physical association between UNC93B and TLRs in the ER is essential for proper TLR signaling.

Abbreviations used in this paper: ATCC, American Type Culture Collection; BM-DC, bone marrow–derived dendritic cell; HEK, human embryonic kidney; HIFS, heat-inactivated fetal calf serum; LPS, lipopolysaccharide; MHC, major histocompatibility complex; MS, mass spectrometry; TEV, Tobacco Etch virus; TIR, Toll-interleukin 1 receptor; TLR, Toll-like receptor.


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