TY - JOUR
T1 - Hvem structures and mutants reveal distinct functions of binding to light and btla/cd160
AU - Liu, Weifeng
AU - Chou, Ting Fang
AU - Garrett-Thomson, Sarah C.
AU - Seo, Goo Young
AU - Fedorov, Elena
AU - Ramagopal, Udupi A.
AU - Bonanno, Jeffrey B.
AU - Wang, Qingyang
AU - Kim, Kenneth
AU - Garforth, Scott J.
AU - Kakugawa, Kiyokazu
AU - Cheroutre, Hilde
AU - Kronenberg, Mitchell
AU - Almo, Steven C.
N1 - Funding Information:
We thank the staff of X29A beam lines at the National Synchrotron Light Source. Graphical abstract was created with BioRender. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract DE-AC02-98CH10886. Data for parts of this study were collected at beamline X29A of the National Synchrotron Light Source. Financial support comes principally from the Offices of Biological and Environmental Research and Basic Energy Sciences of the U.S. Department of Energy and the National Center for Research Resources (P41RR012408) and the National Institute of General Medical Sciences (P41GM103473). Use of the Advanced Photon Source, an Office of Science User Facility op-erated for the U.S. Department of Energy Office of Science by Argonne National Laboratory, was supported by the U.S. Department of Energy under contract DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team (beamline at Sector 31 of the Advanced Photon Source) was provided by Eli Lilly Company, which operates the facility. We also acknowledge support from the Albert Einstein Cancer Center (P30CA013330), the Einstein Crystallographic Core x-ray Diffraction Facility supported by National Institutes of Health Shared Instrumentation Grant S10 OD020068, and the Albert Einstein Macromolecular Therapeutics Development Facility. This work was partially supported by the Price Family Foundation and contributions to the Albert Einstein Center for Experimental Therapeutics by Pamela and Edward S. Pantzer. We thank Jun Zhao and Ella Kothari from transgenic mouse core of the UC San Diego Moores Cancer Center (supported by National Institutes of Health grant P30CA023100); Zbigniew Mikulski, Sara McArdle, Angela Denn, and Katarzyna Dobaczewska from LJI Histology Core (supported by National Institutes of Health grant P30 DK120515 from San Diego Digestive Diseases Research Center); Kristine Suchey, Mindy Hockaday, and the staff from LJI animal facility; and Cheryl Kim from LJI Flow Cytometry Core (supported by National Institutes of Health grant S10RR027366). Support was also provided by National Institutes of Health grants U01 AI125955 and P01 DK46763 (M. Kronenberg) and the Academia Sinica-UC San Diego Talent Development Program (Academia Sinica, Taiwan; T.-F. Chou).
Funding Information:
Department of Energy under contract DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team (beamline at Sector 31 of the Advanced Photon Source) was provided by Eli Lilly Company, which operates the facility. We also acknowledge support from the Albert Einstein Cancer Center (P30CA013330), the Einstein Crystallographic Core x-ray Diffraction Facility supported by National Institutes of Health Shared Instrumentation Grant S10 OD020068, and the Albert Einstein Macromolecular Therapeutics Development Facility. This work was partially supported by the Price Family Foundation and contributions to the Albert Einstein Center for Experimental Therapeutics by Pamela and Edward S. Pantzer. We thank Jun Zhao and Ella Kothari from transgenic mouse core of the UC San Diego Moores Cancer Center (supported by National Institutes of Health grant P30CA023100); Zbigniew Mikulski, Sara McArdle, Angela Denn, and Katarzyna Dobaczewska from LJI Histology Core (supported by National Institutes of Health grant P30 DK120515 from San Diego Digestive Diseases Research Center); Kristine Suchey, Mindy Hockaday, and the staff from LJI animal facility; and Cheryl Kim from LJI Flow Cytometry Core (supported by National Institutes of Health grant S10RR027366). Support was also provided by National Institutes of Health grants U01 AI125955 and P01 DK46763 (M. Kronenberg) and the Academia Sinica-UC San Diego Talent Development Program (Academia Sinica, Taiwan; T.-F. Chou).
Funding Information:
Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract DE-AC02-98CH10886. Data for parts of this study were collected at beamline X29A of the National Synchrotron Light Source. Financial support comes principally from the Offices of Biological and Environmental Research and Basic Energy Sciences of the U.S. Department of Energy and the National Center for Research Resources (P41RR012408) and the National Institute of General Medical Sciences (P41GM103473). Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy Office of Science by Argonne National Laboratory, was supported by the U.S.
Publisher Copyright:
© 2021 Liu et al.
PY - 2021/12/6
Y1 - 2021/12/6
N2 - HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM–LIGHT–CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
AB - HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM–LIGHT–CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
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U2 - 10.1084/jem.20211112
DO - 10.1084/jem.20211112
M3 - Article
C2 - 34709351
AN - SCOPUS:85120704669
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
M1 - e20211112
ER -