Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.
Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.
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DOI：
10.1002/cam4.329
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发表时间：
2014-12
期刊：
影响因子：
4
通讯作者：
Fujii, Masahiro
中科院分区：
文献类型：
--
作者：
Higuchi, Masaya;Takahashi, Masahiko;Tanaka, Yuetsu;Fujii, Masahiro
人T细胞白血病病毒1型（HTLV-1）是成人T细胞白血病的病原体，其在体外以白细胞介素（IL）-2依赖性和IL-2非依赖性的方式永生化和转化原代人T细胞。HTLV-1癌蛋白Tax的表达将小鼠T细胞系CTLL-2的生长从IL-2依赖性转变为IL-2非依赖性。从正常活化的T细胞中撤出IL-2诱导凋亡，这是通过几种促凋亡蛋白（包括Bim）的诱导表达介导的。在这项研究中，我们发现Tax可以保护IL-2耗尽的T细胞免受Bim诱导的凋亡。从CTLL-2细胞中撤出IL-2诱导CTLL-2细胞中Bim蛋白水平的显著增加，但在Tax转化的CTLL-2细胞中没有。Tax转化的CTLL-2细胞中Bim的这种抑制通过两种机制介导：Bim mRNA的下调和Bim蛋白的转录后减少。Tax在CTLL-2细胞中的瞬时表达也抑制IL-2耗竭诱导的Bim表达，然而，Bim蛋白表达的这种降低不是由于Bim mRNA的下调，因此表明Tax转化的CTLL-2中Bim mRNA的下调仅发生在Tax的长期表达之后。Tax在CTLL-2细胞中的瞬时表达也诱导了Erk的激活，然而，这并不参与Bim蛋白的减少。CTLL-2细胞中Bim表达的敲低增强了Tax诱导的IL-2非依赖性转化。HTLV-1感染的人T细胞也降低了它们的Bim蛋白水平，并且在HTLV-1感染的细胞中恢复Bim表达通过诱导凋亡来降低它们的增殖。总之，这些结果表明，Tax诱导的HTLV-1感染的T细胞中Bim的下调促进了它们的IL-2非依赖性生长，从而支持HTLV-1感染在体内的持续性。
Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.
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