The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling.
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.
Brinkmann
Melanie M
MM
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Spooner
Eric
E
Hoebe
Kasper
K
Beutler
Bruce
B
Ploegh
Hidde L
HL
Kim
You-Me
YM
D019943:Amino Acid Substitution; D000818:Animals; D001854:Bone Marrow Cells; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017354:Point Mutation; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C519703:TLR3 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase