Human T-cell leukemia virus type-I oncoprotein Tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of NF-κB
Human T-cell leukemia virus type-I oncoprotein Tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of NF-κB
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DOI：
10.1111/j.1365-2443.2006.00927.x
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发表时间：
2006-02-01
期刊：
影响因子：
2.1
通讯作者：
Yonehara, S
中科院分区：
文献类型：
--
作者：
Okamoto, K;Fujisawa, J;Yonehara, S
人类T细胞白血病病毒I型（HTLV-I）是成人T细胞白血病的病原体，可诱导自身免疫性疾病。先前对Tax转基因小鼠的分析表明，病毒编码的癌蛋白Tax保护外周T细胞免受Fas介导的凋亡与HTLV-I诱导的疾病的发生有关。在这里，我们显示了细胞FLICE/半胱天冬酶-8抑制蛋白（c-FLIP）在Tax表达HTLV-I感染的T细胞中的高水平表达。通过基于慢病毒的RNA干扰系统沉默c-FLIP表达使得Tax阳性HTLV-I感染的T细胞对Fas介导的凋亡敏感。通过使用条件性Cre-loxP介导的诱导系统外源表达的Tax也通过上调HTLV-1阴性T细胞中的c-FLIP表达来抑制Fas介导的细胞凋亡。Tax突变体d3不能激活CREB/ATF 1，而另一个M22突变体不能激活NF-κ B，通过诱导c-FLIP表达抑制Fas介导的凋亡。此外，NF-κ B或I κ B α的显性负突变体的表达不仅取消了c-FLIP表达，而且还取消了Tax对Fas介导的凋亡的抑制活性。然而，NFAT的失活并没有降低HTLV-1感染的T细胞中c-FLIP的表达。总之，Tax通过上调HTLV-1感染细胞中c-FLIP的表达来抑制Fas介导的细胞凋亡，NF-κ B活性在c-FLIP的上调中起重要作用。
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-kappa B did not, suppressed Fas-mediated apoptosis by inducing c-FLIP expression. Furthermore, expression of the dominant negative mutant of either NF-kappa B or I kappa B alpha 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-kappa B activity plays an essential role in the up-regulation of c-FLIP.