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

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  • Melanie M. Brinkmann
    1Whitehead Institute for Biomedical Research, Cambridge, MA 02142
  • Eric Spooner
    1Whitehead Institute for Biomedical Research, Cambridge, MA 02142
  • Kasper Hoebe
    2Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
  • Bruce Beutler
    2Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
  • Hidde L. Ploegh
    1Whitehead Institute for Biomedical Research, Cambridge, MA 02142
  • You-Me Kim
    1Whitehead Institute for Biomedical Research, Cambridge, MA 02142

Description

<jats:p>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.</jats:p>

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