The C-terminal region of tumor necrosis factor like weak inducer of apoptosis is required for interaction with advanced glycation end products

Masahiro Watanabe, Takao Toyomura, Hidenori Wake, Keyue Liu, Kiyoshi Teshigawara, Hideo Takahashi, Masahiro Nishibori, Shuji Mori

Research output: Contribution to journalArticle

Abstract

Previously, we found that endogenously produced pro-inflammatory molecules, advanced glycation end products (AGEs), interact with tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and attenuate its immunomodulatory function. In the present study, to elucidate the mechanism by which AGEs attenuate TWEAK function, we searched for regions responsible for TWEAK–AGE interaction using TWEAK deletion mutants. Pull-down assays with the TWEAK mutants and AGEs revealed that the C-terminal half of TWEAK, which is the region essential for receptor stimulation, was required for this interaction. On the other hand, the N-terminal deletion mutants did not exhibit a significant decrease in AGE binding. Moreover, a moderate decrease in the AGE binding by double-deletion in quartered C-terminal half regions and a substantial decrease by triple-deletion in this region were observed. In addition, full-length TWEAK stimulated IL-8 gene expression in endothelial EA.hy.926 cells, whereas the triple-deletion mutant lost much of this activity, suggesting that the TWEAK–AGE interaction sites overlap with the region needed to exert normal function of TWEAK. Our present findings may help to elucidate the pathophysiological roles of the TWEAK–AGE interaction for prevention and treatment of AGE-related inflammatory diseases.

Original languageEnglish
Pages (from-to)254-260
Number of pages7
JournalBiotechnology and Applied Biochemistry
Volume66
Issue number2
DOIs
Publication statusPublished - Mar 1 2019

Keywords

  • advanced glycation end products
  • binding
  • cytokine
  • deletion mutant
  • tumor necrosis factor like weak inducer of apoptosis

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Molecular Medicine
  • Biomedical Engineering
  • Applied Microbiology and Biotechnology
  • Drug Discovery
  • Process Chemistry and Technology

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