9月5日出版的《分子細(xì)胞》(Molecular Cell)雜志報(bào)道了中國(guó)科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所莫瑋、張亮等同學(xué)的最新研究發(fā)現(xiàn)：在干擾素伽瑪通路中,，β-arrestin1能夠介導(dǎo)該通路中關(guān)鍵轉(zhuǎn)錄因子STAT1與其負(fù)調(diào)節(jié)因子磷酸酶TC45的相互作用,，從而負(fù)調(diào)節(jié)細(xì)胞對(duì)干擾素伽瑪刺激的應(yīng)答，抑制了干擾素伽瑪?shù)目共《咀饔?。這一研究發(fā)現(xiàn)了β-arrestin1蛋白在細(xì)胞核內(nèi)的新功能,，并揭示了STAT1蛋白在細(xì)胞核中的負(fù)調(diào)控機(jī)制。
干擾素伽瑪是機(jī)體內(nèi)具有抗病毒,，抗增殖，免疫調(diào)節(jié)等重要生理功能的細(xì)胞因子,。在機(jī)體經(jīng)受病毒感染時(shí),，干擾素能夠激活體內(nèi)的JAK-STAT1通路，使STAT1發(fā)生酪氨酸磷酸化,，入核,，激活干擾素應(yīng)答基因的轉(zhuǎn)錄，發(fā)揮抗病毒等功能,。
本文第一作者莫瑋,、張亮在胡賡熙研究員指導(dǎo)下，發(fā)現(xiàn)了在干擾素伽瑪刺激下,，β-arrestin1能夠與STAT1核內(nèi)相互作用,，通過(guò)招募酪氨酸磷酸酶TC45到STAT1，從而加速STAT1的去磷酸化,，下調(diào)干擾素伽瑪信號(hào),，抑制其抗病毒活性。STAT1作為干擾素伽瑪通路中最重要的轉(zhuǎn)錄因子,，通過(guò)調(diào)節(jié)基因轉(zhuǎn)錄在抗病毒感染,，抗增殖，免疫調(diào)節(jié)過(guò)程中發(fā)揮重要作用,，STAT1的過(guò)度激活與腫瘤形成,，造血細(xì)胞紊亂都有著密切聯(lián)系。核內(nèi)酪氨酸去磷酸化被認(rèn)為是最重要的STAT1負(fù)調(diào)節(jié)機(jī)制,，本研究的發(fā)現(xiàn)有助于對(duì)STAT1負(fù)調(diào)控機(jī)制更深入的理解,，同時(shí)β-arrestin1核內(nèi)新功能的發(fā)現(xiàn)對(duì)于理解其核內(nèi)分布的重要性有著指導(dǎo)意義。（生物谷Bioon.com）
生物谷推薦原始出處：
Molecular Cell, Vol 31, 695-707, 05 September 2008
Nuclear β-Arrestin1 Functions as a Scaffold for the Dephosphorylation of STAT1 and Moderates the Antiviral Activity of IFN-γ
Wei Mo,1,5 Liang Zhang,1,5 Guohua Yang,1 Jianwei Zhai,1 Zhonghua Hu,1 Yuelei Chen,1Xu Chen,2 Lijian Hui,3 Ruimin Huang,4 and Gengxi Hu1,
1 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2 Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
3 Research Institute of Molecular Pathology, A-1030 Vienna, Austria
4 Department of Neurology, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
Corresponding author
Gengxi Hu
[email protected]
Signal transducers and activators of transcription 1 (STAT1) is activated by tyrosine phosphorylation upon interferon-γ (IFN-γ) stimulation. Phosphorylated STAT1 translocates into nucleus to initiate the transcription of IFN-γ target genes that are important in mediating antiviral, antiproliferative, and immune response. The inactivation of STAT1 is mainly accomplished via tyrosine dephosphorylation by the nuclear isoform of T cell protein tyrosine phosphatase (TC45) in nucleus. Here we show that β-arrestin1 directly interacts with STAT1 in nucleus after IFN-γ treatment and accelerates STAT1 tyrosine dephosphorylation by recruiting TC45. Consequently, β-arrestin1 negatively regulates STAT1 transcription activity as well as the IFN-γ-induced gene transcription. Application of β-arrestin1 siRNA significantly enhances IFN-γ-induced antiviral response in vesicular stomatitis virus (VSV)-infected cells. Our results reveal that nuclear β-arrestin1, acting as a scaffold for the dephosphorylation of STAT1, is an essential negative regulator of IFN-γ signaling and participates in the IFN-γ-induced cellular antiviral response.
