UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5.
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.
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;
Ji-Won
JW
Huh
Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan;
Takuma
T
Shibata
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;
Misun
M
Hwang
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;
Eun-Hye
EH
Kwon
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
Min Seong
MS
Jang
Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan;
Ryutaro
R
Fukui
Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan;Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan; and.
Atsuo
A
Kanno
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;
Da-Jung
DJ
Jung
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; jangmh@ibs.re.kr kmiyake@ims.u-tokyo.ac.jp youmekim@postech.ac.kr.
Myoung Ho
MH
Jang
Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan;Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan; and jangmh@ibs.re.kr kmiyake@ims.u-tokyo.ac.jp youmekim@postech.ac.kr.
Kensuke
K
Miyake
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea jangmh@ibs.re.kr kmiyake@ims.u-tokyo.ac.jp youmekim@postech.ac.kr.
You-Me
YM
Kim
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000166:cytology; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*
D026901:Membrane Transport Proteins; D051198:Toll-Like Receptor 5; C512254:UNC93B1 protein, mouse
3d; Toll-like receptor trafficking