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

Mei Chieh Chen, Ming Jing Hwang, Yang Chieh Chou, Wei Hsu Chen, Genhong Cheng, Hiroyasu Nakano, Tien Yau Luh, Shen Chih Mai, Shie Liang Hsieh

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

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-β receptor (LTβR), 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 LTβR 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 LTβR, but lose the ability to interact with herpes virus entry mediator. By using both LIGHT-R228E and agonistic anti-LTβR monoclonal antibody, we found that signaling triggered by LTβR alone is sufficient to activate both caspase-dependent and caspase-independent pathways. Cross-linking of LTβR 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 LTβR-mediated cell death. This suggests that ASK1 is one of the factors involved in the caspase-independent pathway of LTβR-induced cell death.

Original languageEnglish
Pages (from-to)16073-16081
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
Publication statusPublished - May 2 2003

ASJC Scopus subject areas

  • Biochemistry

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