Human T-cell leukemia virus type-I oncoprotein Tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of NF-kappaB.
Human T-cell leukemia virus type I (HTLV-I) is an etiologic agent of adult T-cell leukemia and induces autoimmune disease. Previous analyses of tax transgenic mice suggested that protection of peripheral T-cells from Fas-mediated apoptosis by virus-encoded oncoprotein Tax was relevant to the onset of HTLV-I-induced diseases. Here, we show the high level expression of cellular FLICE/caspase-8-inhibitory protein (c-FLIP) in Tax-expressing HTLV-I-infected T-cells. The silencing of c-FLIP expression by a lentivirus-based RNA interference system rendered Tax-positive HTLV-I-infected T-cells sensitive to Fas-mediated apoptosis. Exogenously expressed Tax by using a conditional Cre-loxP-mediated inducible system also inhibited Fas-mediated apoptosis by up-regulating c-FLIP expression in HTLV-I-negative T-cells. Tax mutant d3 which cannot activate CREB/ATF1, while another M22 mutant which cannot activate NF-kappaB did not, suppressed Fas-mediated apoptosis by inducing c-FLIP expression. Furthermore, expression of the dominant negative mutant of either NF-kappaB or IkappaBalpha canceled not only c-FLIP expression but also inhibitory activity against Fas-mediated apoptosis by Tax. Inactivation of NFAT, however, did not decrease the expression of c-FLIP in HTLV-I-infected T-cells. Taken together, Tax inhibits Fas-mediated apoptosis by up-regulating c-FLIP expression in HTLV-I-infected cells, and NF-kappaB activity plays an essential role in the up-regulation of c-FLIP.
Okamoto
Kazuo
K
Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
Fujisawa
Jun-ichi
J
Reth
Michael
M
Yonehara
Shin
S
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D034622:RNA Interference; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D016356:Gene Products, tax; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D019014:fas Receptor; D020169:Caspases