Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells.
Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells.
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DOI：
10.1073/pnas.1715724115
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发表时间：
2018-02-06
影响因子：
11.1
通讯作者：
Matsuoka M
中科院分区：
文献类型：
--
作者：
Mahgoub M;Yasunaga JI;Iwami S;Nakaoka S;Koizumi Y;Shimura K;Matsuoka M
致癌逆转录病毒人类t细胞白血病病毒1型（HTLV-1）编码Tax，这是一种病毒复制和细胞致癌途径的激活剂。尽管Tax具有强大的活性，但其在发病机制中的确切作用仍不清楚，因为它在体内表达微弱。这项研究表明，在htlv -1诱导的白血病细胞的一小部分亚群中观察到零星和短暂的Tax表达。这种有限的Tax表达通过点燃抗凋亡信号对整个群体的生存至关重要。Tax可由多种应激诱导，这表明在细胞应激条件下，Tax可有效保护细胞免于凋亡，并从病毒库中重新激活病毒。这是HTLV-1逃避宿主免疫并在体内持续存在的一种精心设计的策略。引起慢性感染的病毒巧妙地操纵被感染的细胞，使病毒在免疫压力下在体内持续存在。人T细胞白血病病毒1型（HTLV-1）在体内主要在CD4+ T细胞中建立持续感染并诱导该亚群白血病。htlv -1编码的Tax是病毒复制的关键反激活因子和一种有效的癌蛋白，但由于其在体内的表达水平非常低，其在发病机制中的意义尚不清楚。在这里，我们表明在任何给定时间，Tax在一小部分白血病细胞中表达，重要的是，它的表达自发地在开和关状态之间切换。活细胞成像显示，一次Tax表达的平均持续时间为~ 19小时。在大多数细胞中，敲低Tax可迅速诱导细胞凋亡，这表明即使其短期表达仅限于一小部分亚群，但Tax对维持细胞群至关重要。单细胞分析和计算模拟表明，短暂的Tax表达触发抗凋亡机制，即使在Tax表达减少后，这种作用仍在继续；这种抗凋亡机制的激活是维持种群的关键事件。此外，Tax可被各种细胞毒性胁迫诱导，并促进HTLV-1的复制。因此，Tax似乎可以保护受感染的细胞免于凋亡，并在关键时刻增加病毒传播的机会。因此，使Tax的表达保持在最低水平，但可根据需要诱导，是HTLV-1促进持续感染和白血病发生的基本策略。
The oncogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1) encodes Tax, an activator of both viral replication and cellular oncogenic pathways. Despite the potent activities of Tax, its precise roles in pathogenesis remain unclear, since it is faintly expressed in vivo. This study shows that sporadic and transient Tax expression is observed in a small subpopulation of HTLV-1–induced leukemic cells. This limited Tax expression is critical for survival of the whole population through ignition of antiapoptotic signals. Tax is induced by various stresses, suggesting that Tax efficiently protects cells from apoptosis and reactivates virus from reservoirs under conditions of cellular stress. It is an elaborated strategy of HTLV-1 to evade host immunity and enable persistence in vivo. Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1–encoded Tax is a critical transactivator of viral replication and a potent oncoprotein, but its significance in pathogenesis remains obscure due to its very low level of expression in vivo. Here, we show that Tax is expressed in a minor fraction of leukemic cells at any given time, and importantly, its expression spontaneously switches between on and off states. Live cell imaging revealed that the average duration of one episode of Tax expression is ∼19 hours. Knockdown of Tax rapidly induced apoptosis in most cells, indicating that Tax is critical for maintaining the population, even if its short-term expression is limited to a small subpopulation. Single-cell analysis and computational simulation suggest that transient Tax expression triggers antiapoptotic machinery, and this effect continues even after Tax expression is diminished; this activation of the antiapoptotic machinery is the critical event for maintaining the population. In addition, Tax is induced by various cytotoxic stresses and also promotes HTLV-1 replication. Thus, it seems that Tax protects infected cells from apoptosis and increases the chance of viral transmission at a critical moment. Keeping the expression of Tax minimal but inducible on demand is, therefore, a fundamental strategy of HTLV-1 to promote persistent infection and leukemogenesis.
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影响因子：
5.2
作者：
Kannagi M;Hasegawa A;Takamori A;Kinpara S;Utsunomiya A
通讯作者：
Utsunomiya A
影响因子：
5.4
作者：
Kinjo, Takao;Ham-Terhune, Julia;Jeang, Kuan-Teh
通讯作者：
Jeang, Kuan-Teh
DOI：
10.1098/rstb.2016.0272
发表时间：
2017-10-19
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Bangham CRM;Matsuoka M
通讯作者：
Matsuoka M
影响因子：
3.3
作者：
Boxus M;Twizere JC;Legros S;Dewulf JF;Kettmann R;Willems L
通讯作者：
Willems L
影响因子：
20.3
作者：
Dassouki, Zeina;Sahin, Umut;Bazarbachi, Ali
通讯作者：
Bazarbachi, Ali