TY - JOUR
T1 - Cryo-EM structures of Toll-like receptors in complex with UNC93B1
AU - Ishida, Hanako
AU - Asami, Jinta
AU - Zhang, Zhikuan
AU - Nishizawa, Tomohiro
AU - Shigematsu, Hideki
AU - Ohto, Umeharu
AU - Shimizu, Toshiyuki
N1 - Funding Information:
We thank A. Tsutsumi, Y. Sakamaki, M. Kikkawa (Cryo-EM facility in the University of Tokyo) and M. Yamamoto (RIKEN RSC Cryo-EM facility) for their help in cryo-EM data collection. We thank R. Fukui and K. Miyake for their helpful discussion on this manuscript. This work was supported by a Grant-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology grant nos. 20K16274 (H.I.), 26711002 (U.O.) and 19H00976 (T.S.); CREST, JST (T.S.); the Takeda Science Foundation (U.O. and T.S.); the Mochida Memorial Foundation for Medical and Pharmaceutical Research (U.O.); the Daiichi Sankyo Foundation of Life Science (U.O.); the Uehara Memorial Foundation (U.O. and T.S.); and the Naito Foundation (U.O. and T.S.). This work is partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from Japan Agency for Medical Research and Development (AMED) under grant number JP19am0101115, JP19am0101070 (to H.S.). This work was supported in part by the RIKEN Dynamic Structural Biology project (to H.S.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/2
Y1 - 2021/2
N2 - Nucleic acid–sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3–UNC93B1 complexes and a human TLR7–UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.
AB - Nucleic acid–sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3–UNC93B1 complexes and a human TLR7–UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.
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U2 - 10.1038/s41594-020-00542-w
DO - 10.1038/s41594-020-00542-w
M3 - Article
C2 - 33432245
AN - SCOPUS:85099097400
SN - 1545-9993
VL - 28
SP - 173
EP - 180
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 2
ER -
