生物谷报道：来自UCLA的Jonsson 癌症中心的科学家们最近发现了一种全新的抗炎细胞信号通路，这或许是保持免疫反应精确平衡的重要机制。
研究结果发表在6月份的Cell上，UCLA的血液学及肿瘤学教授，文章第一作者Ke Shuai认为，研究成果将带来新的治疗癌症和炎症反应疾病的方法。
Shuai表示：“研究的重要成果在于发现了新的限制炎症和免疫的细胞路径。免疫系统对于对抗病原感染和杀死肿瘤细胞都很重要。这一发现能帮助我们设计新的调节免疫系统的药物。”
Shuai和同事发现了这种PIAS1抗炎路径，这是一种常被广泛的刺激物用来调解免疫系统并且触发炎症的路径。发炎是身体的一种对抗感染的自然防御，但是不平衡的炎症将使人们更易患上癌症等疾病。
PIAS1路径帮助保持免疫系统的健康平衡。当遇到细菌和其它威胁时，重要的免疫调控基因将在细胞核中启动以对抗感染。Shuai和同事则发现，PIAS1能阻止免疫调控基因的产物，以防止产生过度炎症反应。
在发生癌症时，免疫系统能被动员起来杀死癌细胞，这可以帮助研发抗癌疫苗。因此，一种能够减弱PIAS1路径的药物就可以用于增强免疫系统对抗癌症作用。除此之外，这类药物还可以对抗其它重要疾病，例如HIV等。
Shuai的研究小组下一步计划是研究利用小型化学分子来作用于PIAS1信号通路，从而达到治疗癌症和其它疾病的效果。 （引自教育部科技发展中心）
英文原文链接：http://www.physorg.com/news100527374.html
原始出处:
Cell, Vol 129, 903-914, 01 June 2007
Article
Proinflammatory Stimuli Induce IKKα-Mediated Phosphorylation of PIAS1 to Restrict Inflammation and Immunity
Bin Liu,1,8 Yonghui Yang,1,8 Vasili Chernishof,1 Rachel R. Ogorzalek Loo,2,3,4 Hyunduk Jang,1 Samuel Tahk,3 Randy Yang,2 Sheldon Mink,2 David Shultz,6 Clifford J. Bellone,7 Joseph A. Loo,2,3,4,5 and Ke Shuai1,2,3,
1 Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
2 Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA
3 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA
4 UCLA-DOE Institute of Genomics and Proteomics, University of California Los Angeles, Los Angeles, CA 90095, USA
5 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA
6 Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
7 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
Corresponding author
Ke Shuai
kshuai@mednet.ucla.edu
Summary
How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-κB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-κB target genes. Furthermore, IKKα, but not IKKβ, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKα-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.
