Inhibition of lymphotoxin-beta receptor-mediated cell death by survivin-DeltaEx3.
TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-beta receptor (LTbetaR) to induce cell death via caspase-dependent and caspase-independent pathways. It has been shown that cellular inhibitor of apoptosis protein-1 inhibits cell death by binding to LTbetaR-TRAF2/TRAF3 complexes and caspases. In this study, we found that both Kaposi's sarcoma-associated herpesvirus K7 (KSHV-K7), a viral inhibitor of apoptosis protein, and the structurally related protein survivin-DeltaEx3 could inhibit LTbetaR-mediated caspase-3 activation. However, only survivin-DeltaEx3 could protect cells from LTbetaR-mediated cell death. The differential protective effects of survivin-DeltaEx3 and KSHV-K7 can be attributed to the fact that survivin-DeltaEx3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-DeltaEx3 is able to inhibit production of reactive oxygen species and can translocate from nucleus to cytosol to associate with apoptosis signal-regulating kinase 1 after activation of LTbetaR. Furthermore, survivin-DeltaEx3 protects LTbetaR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-DeltaEx3 is able to regulate both caspase-dependent and caspase-independent pathways, whereas inhibition of caspase-independent pathway is both sufficient and necessary for its protective effect on LTbetaR-mediated cell death.
Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Ren-In
RI
You
Mei-Chieh
MC
Chen
Hsei-Wei
HW
Wang
Yang-Chieh
YC
Chou
Chi-Hung
CH
Lin
Shie-Liang
SL
Hsieh
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D006528:Carcinoma, Hepatocellular; D053148:Caspase 3; D061945:Caspase Inhibitors; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053259:Lymphotoxin beta Receptor; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction; D000077022:Survivin; D014162:Transfection; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C468524:K7 protein, Human herpesvirus 8; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D000077022:Survivin; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019938:Cyclin D1; D007371:Interferon-gamma; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C505407:CASP3 protein, human; D053148:Caspase 3