9月5日出版的《分子细胞》(Molecular Cell)杂志报道了中国科学院上海生命科学研究院生物化学与细胞生物学研究所莫玮、张亮等同学的最新研究发现：在干扰素伽玛通路中，β-arrestin1能够介导该通路中关键转录因子STAT1与其负调节因子磷酸酶TC45的相互作用，从而负调节细胞对干扰素伽玛刺激的应答，抑制了干扰素伽玛的抗病毒作用。这一研究发现了β-arrestin1蛋白在细胞核内的新功能，并揭示了STAT1蛋白在细胞核中的负调控机制。
干扰素伽玛是机体内具有抗病毒，抗增殖，免疫调节等重要生理功能的细胞因子。在机体经受病毒感染时，干扰素能够激活体内的JAK-STAT1通路，使STAT1发生酪氨酸磷酸化，入核，激活干扰素应答基因的转录，发挥抗病毒等功能。
本文第一作者莫玮、张亮在胡赓熙研究员指导下，发现了在干扰素伽玛刺激下，β-arrestin1能够与STAT1核内相互作用，通过招募酪氨酸磷酸酶TC45到STAT1，从而加速STAT1的去磷酸化，下调干扰素伽玛信号，抑制其抗病毒活性。STAT1作为干扰素伽玛通路中最重要的转录因子，通过调节基因转录在抗病毒感染，抗增殖，免疫调节过程中发挥重要作用，STAT1的过度激活与肿瘤形成，造血细胞紊乱都有着密切联系。核内酪氨酸去磷酸化被认为是最重要的STAT1负调节机制，本研究的发现有助于对STAT1负调控机制更深入的理解，同时β-arrestin1核内新功能的发现对于理解其核内分布的重要性有着指导意义。（生物谷Bioon.com）
生物谷推荐原始出处：
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
gxhu@sibs.ac.cn
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.
