The role of apoptosis signal-regulating kinase 1 in lymphotoxin-beta receptor-mediated cell death.
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.
Chen
Mei-Chieh
MC
Institute and Department of Microbiology and Immunology, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan.
Hwang
Ming-Jing
MJ
Chou
Yang-Chieh
YC
Chen
Wei-Hsu
WH
Cheng
Genhong
G
Nakano
Hiroyasu
H
Luh
Tien-Yau
TY
Mai
Shen-Chih
SC
Hsieh
Shie-Liang
SL
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D006801:Humans; D053259:Lymphotoxin beta Receptor; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D011506:Proteins / Q000502:physiology; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014407:Tumor Cells, Cultured; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D020169:Caspases