An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-κB Activation
An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-κB Activation
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DOI：
10.1128/jvi.06456-11
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发表时间：
2012-03-01
影响因子：
5.4
通讯作者：
Harhaj, Edward W.
中科院分区：
文献类型：
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作者：
Lavorgna, Alfonso;Harhaj, Edward W.
人类T细胞白血病病毒1型(HTLV-1)Tax癌蛋白活跃地穿梭于细胞核和细胞质之间，在那里它与转录和剪接调节蛋白相互作用，并在胞浆中激活核因子-kappaB。TAX的翻译后修饰，如泛素化，调节其亚细胞定位，从而调节其功能；然而，宿主因素对税收转运和核因子-kappa B激活的调控知之甚少。通过筛选去泛素化(DUB)酶小干扰RNA(SiRNA)文库，我们鉴定了金属蛋白酶STAM结合蛋白样蛋白1(STAMBPL1)是Tax介导的NF-kappa B激活的正调控因子。野生型STAMBPL1的过表达，但不是催化失活的突变体，增强了Tax介导的NF-kappa B的激活，而用siRNA沉默STAMBPL1则削弱了正则和非正则的NF-kappa B信号通路的Tax激活。STAMBPL1通过控制税收核/细胞质转运间接调节税收诱导的核转录因子-kappaB信号，是DNA损伤诱导税收核出口所必需的。综上所述，这些结果揭示了脱泛素酶STAMBPL1是税收交易和功能的关键调节因子。
The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein actively shuttles between the nucleus, where it interacts with transcriptional and splicing regulatory proteins, and the cytoplasm, where it activates NF-kappa B. Posttranslational modifications of Tax such as ubiquitination regulate its subcellular localization and hence its function; however, the regulation of Tax trafficking and NF-kappa B activation by host factors is poorly understood. By screening a deubiquitinating (DUB) enzyme small interfering RNA (siRNA) library, we identified the metalloprotease STAM-binding protein-like 1 (STAMBPL1) as a positive regulator of Tax-mediated NF-kappa B activation. Overexpression of wild-type STAMBPL1, but not a catalytically inactive mutant, enhanced Tax-mediated NF-kappa B activation, whereas silencing of STAMBPL1 with siRNA impaired Tax activation of both the canonical and non-canonical NF-kappa B signaling pathways. STAMBPL1 regulated Tax-induced NF-kappa B signaling indirectly by controlling Tax nuclear/cytoplasmic transport and was required for DNA damage-induced Tax nuclear export. Together, these results reveal that the deubiquitinase STAMBPL1 is a key regulator of Tax trafficking and function.