Hvem structures and mutants reveal distinct functions of binding to light and btla/cd160

Weifeng Liu, Ting Fang Chou, Sarah C. Garrett-Thomson, Goo Young Seo, Elena Fedorov, Udupi A. Ramagopal, Jeffrey B. Bonanno, Qingyang Wang, Kenneth Kim, Scott J. Garforth, Kiyokazu Kakugawa, Hilde Cheroutre, Mitchell Kronenberg, Steven C. Almo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere20211112
JournalJournal of Experimental Medicine
Volume218
Issue number12
DOIs
StatePublished - Dec 6 2021

ASJC Scopus subject areas

  • Medicine(all)

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