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The role of apoptosis signal-regulating kinase 1 in lymphotoxin-beta receptor-mediated cell death.

Authors
  • Chen, Mei-Chieh
  • Hwang, Ming-Jing
  • Chou, Yang-Chieh
  • Chen, Wei-Hsu
  • Cheng, Genhong
  • Nakano, Hiroyasu
  • Luh, Tien-Yau
  • Mai, Shen-Chih
  • Hsieh, Shie-Liang
Type
Published Article
Journal
The Journal of biological chemistry
Publication Date
May 02, 2003
Volume
278
Issue
18
Pages
16073–16081
Identifiers
PMID: 12566458
Source
Medline
License
Unknown

Abstract

LIGHT (homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes) is a member of the tumor necrosis factor superfamily that can interact with lymphotoxin-beta receptor (LTbetaR), herpes virus entry mediator, and decoy receptor (DcR3). In our previous study, we showed that LIGHT is able to induce cell death via the non-death domain containing receptor LTbetaR to activate both caspase-dependent and caspase-independent pathway. In this study, a LIGHT mutein, LIGHT-R228E, was shown to exhibit similar binding specificity as wild type LIGHT to LTbetaR, but lose the ability to interact with herpes virus entry mediator. By using both LIGHT-R228E and agonistic anti-LTbetaR monoclonal antibody, we found that signaling triggered by LTbetaR alone is sufficient to activate both caspase-dependent and caspase-independent pathways. Cross-linking of LTbetaR is able to recruit TRAF3 and TRAF5 to activate ASK1, whereas its activity is inhibited by free radical scavenger carboxyfullerenes. The activation of ASK1 is independent of caspase-3 activation, and kinase-inactive ASK1-KE mutant can inhibit LTbetaR-mediated cell death. This suggests that ASK1 is one of the factors involved in the caspase-independent pathway of LTbetaR-induced cell death.

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