Activation of nuclear factor of activated T cells by human T-Lymphotropic virus type 1 accessory protein p12I
Activation of nuclear factor of activated T cells by human T-Lymphotropic virus type 1 accessory protein p12I
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DOI：
10.1128/jvi.76.7.3493-3501.2002
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发表时间：
2002-04-01
影响因子：
5.4
通讯作者：
Lairmore, MD
中科院分区：
文献类型：
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作者：
Albrecht, B;D'Souza, CD;Lairmore, MD
人类嗜T淋巴病毒1型（HTLV-1）是CD4(+) T淋巴细胞侵袭性恶性肿瘤的病原体，称为成人T细胞淋巴瘤/白血病，并与许多免疫介导的疾病有关。为了建立感染，HTLV-1必须在感染的早期阶段激活靶向T细胞。我们最近证明HTLV-1附属蛋白p12(I)对于体内持续感染和静止原发淋巴细胞的病毒感染至关重要，这表明p12(I)在淋巴细胞活化中起作用。为了测试p12(I)是否调节T淋巴细胞活化所需的信号通路，我们在表达p12(I)的Jurkat T细胞中检测了AP-1-、NT-kappaB-和活化T细胞核因子（NFAT）驱动的报告基因活性，并与载体转染的对照细胞进行了比较。HTLV-1 p12(I)特异性诱导nfat介导的转录，与Ras/丝裂原激活的蛋白激酶途径协同作用约20倍，但不影响AP-1或nf - kappab依赖的基因表达。环菌素A、BAPTA-AM[甘氨酸，N，N'-1,2-乙基酰基双（氧-2,1-苯基）-双-N-2-（乙酰氧基）甲氧基-2-氧乙基]-[双（乙酰氧基）甲酯]-[双（乙酰氧基）甲酯]-抑制钙依赖信号，以及NFAT2显性负突变体可消除p12(I)介导的nfat依赖性转录激活。相反，抑制磷脂酶c - γ和LAT （T细胞活化的连接物）不会影响p12(I)诱导的NFAT活性。重要的是，p12(I)在功能上取代了thapsigargin，后者选择性地消耗细胞内钙储存。我们的数据首次证明了HTLV-1 p12(I)在淋巴样细胞中nfat介导的钙依赖性转录激活中的作用。我们提出了一种新的机制，HTLV-1，一种与淋巴增生性疾病相关的病毒，通过失调常见的t细胞激活途径，对病毒建立持续感染至关重要。
Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4(+) T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12(I) is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12(I) in lymphocyte activation. To test whether p12(I) modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NT-kappaB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12(I)-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12(I) specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-kappaB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N'-1,2-ethanedlylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis (acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12(I)-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-gamma and LAT (linker for activation of T cells) did not affect p12(I)-induced NFAT activity. Importantly, p12(I) functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12(I) in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.