HTLV-1 HBZ Protein Resides Exclusively in the Cytoplasm of Infected Cells in Asymptomatic Carriers and HAM/TSP Patients
HTLV-1 HBZ Protein Resides Exclusively in the Cytoplasm of Infected Cells in Asymptomatic Carriers and HAM/TSP Patients
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DOI：
10.3389/fmicb.2019.00819
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发表时间：
2019-04-26
影响因子：
5.2
通讯作者：
Accolla, Roberto S.
中科院分区：
文献类型：
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作者：
Forlani, Greta;Baratella, Marco;Accolla, Roberto S.
人类T细胞嗜淋巴细胞病毒1型（HTLV-1）是成人T细胞白血病/淋巴瘤（ATL）和HTLV-1相关脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）的病原体。两种病毒蛋白Tax-1和HTLV-1碱性亮氨酸拉链因子（HBZ）在这两种疾病的发病机制中起重要作用。我们最近证明，HBZ，以前被认为是一种核蛋白，是专门定位于HAM/TSP患者的外周血单核细胞（PBMC）的细胞质。在这里，对更大的HAM/TSP病例组的分析证实了HBZ是细胞质蛋白，而Tax-1优先定位于细胞质中，细胞核中具有较少的斑点样点。更重要的是，在这里我们首次报道了HBZ在无症状携带者（AC）中表达时也局限于细胞质中。类似地，Tax-1在AC的显著比例中优先在细胞质中表达。有趣的是，在HAM/TSP和AC患者中，在同一细胞中很少发现HBZ和Tax-1的表达。我们观察到只有少数情况下，共表达两种癌蛋白在一个非常有限的细胞数量。在代表性AC和HAM/TSP患者中，表达细胞质HBZ的细胞几乎仅见于CD 4 + T细胞区室，而在CD 8 + T细胞中很少。有趣的是，至少在分析的病例中，胸腺细胞表达的参与选择的分子（THEMIS）的表达与AC和HAM/TSP中HBZ的细胞质定位无关。对从HAM/TSP患者建立的HTLV-1永生化细胞系的研究证实了HBZ是一种不穿梭于细胞质和细胞核之间的常驻细胞质蛋白。这些结果扩展了我们以前对HAM/TSP和ATL之间HBZ定位的二分法的观察，分别指向两种疾病状态中的细胞质或细胞核定位。此外，它们在HBZ或Tax-1的不同细胞中显示出相当选择性的表达。HBZ仅在AC的细胞质中表达这一前所未有的观察结果强烈表明，在与HTLV-1感染相关的疾病状态期间，HBZ定位进行性改变。未来的研究将阐明不同的HBZ细胞内定位是否是一个标志物或疾病演变的致病事件。
Human T cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. Two viral proteins, Tax-1 and HTLV-1 basic leucine zipper factor (HBZ), play important roles in the pathogenesis of both diseases. We recently demonstrated that HBZ, previously considered a nuclear protein, is exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients. Here, the analysis of a larger panel of HAM/TSP cases confirmed that HBZ is a cytoplasmic protein, while Tax-1 preferentially localized in the cytoplasm with fewer speckle-like dots in the nucleus. More importantly, here we report for the first time that HBZ, when expressed in asymptomatic carriers (AC), is also confined in the cytoplasm. Similarly, Tax-1 was preferentially expressed in the cytoplasm in a significant proportion of AC. Interestingly, in both HAM/TSP and AC patients, the expression of HBZ and Tax-1 was rarely found in the same cell. We observed only few cases coexpressing the two oncoprotein in a very limited number of cells. In representative AC and HAM/TSP patients, cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment and very rarely in CD8+ T cells. Interestingly, at least in the cases analyzed, the expression of thymocite-expressed molecule involved in selection (THEMIS) is dispensable for the cytoplasmic localization of HBZ in both AC and HAM/TSP. The study of an HTLV-1-immortalized cell line established from an HAM/TSP patient confirmed HBZ as a resident cytoplasmic protein not shuttling between the cytoplasm and nucleus. These results extend our previous observation on the dichotomy of HBZ localization between HAM/TSP and ATL, pointing to the exclusive either cytoplasmic or nuclear localization in the two diseased states, respectively. Moreover, they show a rather selective expression in distinct cells of either HBZ or Tax-1. The unprecedented observation that HBZ is expressed only in the cytoplasm in AC strongly suggests a progressive modification of HBZ localization during the disease states associated to HTLV-1 infection. Future studies will clarify whether the distinct HBZ intracellular localization is a marker or a causative event of disease evolution.