9月5日出版的《分子細胞》(Molecular Cell)雜志報道了中國科學院上海生命科學研究院生物化學與細胞生物學研究所莫瑋,、張亮等同學的最新研究發(fā)現(xiàn)：在干擾素伽瑪通路中,，β-arrestin1能夠介導該通路中關鍵轉錄因子STAT1與其負調(diào)節(jié)因子磷酸酶TC45的相互作用,，從而負調(diào)節(jié)細胞對干擾素伽瑪刺激的應答，抑制了干擾素伽瑪?shù)目共《咀饔?。這一研究發(fā)現(xiàn)了β-arrestin1蛋白在細胞核內(nèi)的新功能,，并揭示了STAT1蛋白在細胞核中的負調(diào)控機制。
干擾素伽瑪是機體內(nèi)具有抗病毒,，抗增殖,，免疫調(diào)節(jié)等重要生理功能的細胞因子。在機體經(jīng)受病毒感染時,，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,，激活干擾素應答基因的轉錄，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,，抑制其抗病毒活性。STAT1作為干擾素伽瑪通路中最重要的轉錄因子,，通過調(diào)節(jié)基因轉錄在抗病毒感染,，抗增殖，免疫調(diào)節(jié)過程中發(fā)揮重要作用,，STAT1的過度激活與腫瘤形成,，造血細胞紊亂都有著密切聯(lián)系。核內(nèi)酪氨酸去磷酸化被認為是最重要的STAT1負調(diào)節(jié)機制,，本研究的發(fā)現(xiàn)有助于對STAT1負調(diào)控機制更深入的理解,，同時β-arrestin1核內(nèi)新功能的發(fā)現(xiàn)對于理解其核內(nèi)分布的重要性有著指導意義。（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.
