Molecular mechanism of aberrant activation of cytokine expressions and immunodeficiency by HTLV-1 infection

HTLV-1感染导致细胞因子表达异常激活和免疫缺陷的分子机制

• 批准号: 17590983
• 负责人: MASAHIRO Fujii
• 金额: $ 2.24万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590983/
• 关键词: HTLV-1; Virus; leukemia; ATL; NF-kB; NFAT; Tax; 微生物; サイトカイン; Tax; NFAT; IL-2; AP-1

Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia (ATL), and the distinct pathogenecity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. We found two crucial differences between Tax1 and Tax2. 1, Tax1 but not Tax2 interacts with NF-kB2/p100, and activates it by inducing the cleavage of p100 into the active transcription factor, p52. The RNA interference method demonstrated that NF-kB2/p100 is required for the transformation induced by Tax1 but not Tax2, as determined by their ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2) dependent growth into independent growth. While Tax2 showed a reduced transforming activity relative to Tax1, a Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 showed an equivalent transforming activity to Tax1 in CTLL-2 expressing an inducer of p52 processing (an active form of NF-κB inducing kinase). These results reveal the activation of NF-κB2/p100 to play a crucial role in the Tax1-mediated transformation of T-cells, and NF-κB2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2. 2, Tax2 stimulated gene expression of interleukin (IL)-2 through the nuclear factor of activated T cells (NFAT). However, the activity of HTLV-1 Tax1 was minimal in this system. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells.Our results suggest that the distinct transformation mechanism of Tax1 relative to Tax2 play crucial role in HTLV-1 specific leukemogenesis.

人类 T 细胞白血病病毒 1 型 (HTLV-1) 而不是 HTLV-2 与成人 T 细胞白血病 (ATL) 相关，这两种密切相关的病毒的不同致病性被认为源于其不同的生物学功能。我们发现 Tax1 和 Tax2 各自的转化蛋白 HTLV-1 Tax1 和 HTLV-2 Tax2 之间存在两个关键差异，Tax1 但不与 Tax2 相互作用。 RNA 干扰方法证明，Tax1 而非 Tax2 诱导的转化需要 NF-kB2/p100，并通过诱导 p100 裂解为活性转录因子 p52 来激活它。将 T 细胞系 (CTLL-2) 从白细胞介素 2 (IL-2) 依赖性生长转化为独立生长的能力，而 Tax2 相对于 Tax1 表现出较低的转化活性，与仅存在于 Tax1 中的 PDZ 结构域结合基序 (PBM) 融合的 Tax2 在表达 p52 加工诱导剂（NF-κB 诱导激酶的活性形式）的 CTLL-2 中显示出与 Tax1 相当的转化活性。这些结果揭示了激活作用。 NF-κB2/p100 在 Tax1 介导的 T 细胞转化中发挥关键作用，NF-κB2/p100 激活和 PBM 功能均负责增强转化Tax1 相对​​于 Tax2 的活性。2、Tax2 通过活化 T 细胞的核因子 (NFAT) 刺激白细胞介素 (IL)-2 的基因表达，但在该系统中 HTLV-1 Tax1 的活性很小。一种 NFAT 激活抑制剂，可消除 HTLV-2 永生化 T 细胞系中 IL-2 mRNA 的诱导，并同时抑制细胞生长。此外，抗 IL-2 受体抗体显着降低了 HTLV-2 感染的 T 细胞系的增殖，但不降低 HTLV-1 感染的细胞的增殖。我们的结果表明，Tax1 相对​​于 Tax2 的独特转化机制在 HTLV-1 特异性白血病发生中起着至关重要的作用。

项目成果

Aberrant Activation of the Interleukin 2 Autocrine Loop through Nuclear Factor of Activated T cells by Nonleukemogenic Human T-cell Leukemia Virus Type 2 but not Leukemogenic Type 1 Virus

非致白血病人类 T 细胞白血病病毒 2 型而非致白血病 1 型病毒通过激活 T 细胞的核因子异常激活白细胞介素 2 自分泌环

• 发表时间: 2005
• 期刊: J.Virol. 79(18)
• 作者: Masahiro Morita;Toru Suzuki;Kentaro Ito;Tadashi Yamamoto;Hall WW;Niinuma A
• 通讯作者: Niinuma A

Deregulation of cell-signaling pathways in HTLV-1 infection

• DOI: 10.1038/sj.onc.1208975
• 发表时间: 2005-09-05
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Hall, WW;Fujii, M
• 通讯作者: Fujii, M

Nucleotide sequences and functions of the Epstein-Barr virus latent membrane protein 1 genes isolated from salivary gland lymphoepithelial carcinomas

从唾液腺淋巴上皮癌中分离出的 Epstein-Barr 病毒潜伏膜蛋白 1 基因的核苷酸序列和功能

• 发表时间: 2005
• 期刊: Virus Genes 30(2)
• 作者: Masahiro Morita;Toru Suzuki;Kentaro Ito;Tadashi Yamamoto;Hall WW;Niinuma A;Tsubata C;Higuchi M;Kawakami H;Jen KY
• 通讯作者: Jen KY

Inactivation of tumor suppressor Dlg1 augments interleukin-2 independent transformation of a T-cell line induced by human T-cell leukemia virus type 1 Tax protein

肿瘤抑制因子 Dlg1 失活可增强人 T 细胞白血病病毒 1 型 Tax 蛋白诱导的 T 细胞系的不依赖白细胞介素 2 的转化

• 发表时间: 2006
• 期刊: Retrovirology 3
• 作者: Fukuno K;Takahashi S;Tojo A;et al.;Ishioka K
• 通讯作者: Ishioka K

Human T-cell leukemia virus type 2 Tax protein induces interleukin 2-independent growth in a T-cell line

• DOI: 10.1186/1742-4690-3-88
• 发表时间: 2006-12-02
• 期刊: RETROVIROLOGY
• 影响因子: 3.3
• 作者: Kondo, Rie;Higuchi, Masaya;Fujii, Masahiro
• 通讯作者: Fujii, Masahiro