HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

Author:

Liu Weifeng1ORCID,Chou Ting-Fang2ORCID,Garrett-Thomson Sarah C.1ORCID,Seo Goo-Young2ORCID,Fedorov Elena1ORCID,Ramagopal Udupi A.1ORCID,Bonanno Jeffrey B.1ORCID,Wang Qingyang2ORCID,Kim Kenneth2ORCID,Garforth Scott J.1ORCID,Kakugawa Kiyokazu3ORCID,Cheroutre Hilde23ORCID,Kronenberg Mitchell24ORCID,Almo Steven C.15ORCID

Affiliation:

1. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY

2. La Jolla Institute for Immunology, La Jolla, CA

3. Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

4. Division of Biological Sciences, University of California San Diego, La Jolla, CA

5. Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY

Abstract

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.

Funder

U.S. Department of Energy

National Center for Research Resources

National Institute of General Medical Sciences

Eli Lilly Company

Albert Einstein Cancer Center

National Institutes of Health

Albert Einstein Macromolecular Therapeutics Development Facility

Price Family Foundation

Albert Einstein Center for Experimental Therapeutics

Pamela and Edward S. Pantzer

Academia Sinica

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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