生物谷報道：來自UCLA的Jonsson 癌癥中心的科學(xué)家們最近發(fā)現(xiàn)了一種全新的抗炎細(xì)胞信號通路,，這或許是保持免疫反應(yīng)精確平衡的重要機(jī)制。
研究結(jié)果發(fā)表在6月份的Cell上,，UCLA的血液學(xué)及腫瘤學(xué)教授,，文章第一作者Ke Shuai認(rèn)為,，研究成果將帶來新的治療癌癥和炎癥反應(yīng)疾病的方法。
Shuai表示：“研究的重要成果在于發(fā)現(xiàn)了新的限制炎癥和免疫的細(xì)胞路徑,。免疫系統(tǒng)對于對抗病原感染和殺死腫瘤細(xì)胞都很重要,。這一發(fā)現(xiàn)能幫助我們設(shè)計新的調(diào)節(jié)免疫系統(tǒng)的藥物。”
Shuai和同事發(fā)現(xiàn)了這種PIAS1抗炎路徑,，這是一種常被廣泛的刺激物用來調(diào)解免疫系統(tǒng)并且觸發(fā)炎癥的路徑,。發(fā)炎是身體的一種對抗感染的自然防御，但是不平衡的炎癥將使人們更易患上癌癥等疾病,。
PIAS1路徑幫助保持免疫系統(tǒng)的健康平衡,。當(dāng)遇到細(xì)菌和其它威脅時，重要的免疫調(diào)控基因?qū)⒃诩?xì)胞核中啟動以對抗感染,。Shuai和同事則發(fā)現(xiàn),，PIAS1能阻止免疫調(diào)控基因的產(chǎn)物，以防止產(chǎn)生過度炎癥反應(yīng),。
在發(fā)生癌癥時,，免疫系統(tǒng)能被動員起來殺死癌細(xì)胞，這可以幫助研發(fā)抗癌疫苗,。因此,，一種能夠減弱PIAS1路徑的藥物就可以用于增強(qiáng)免疫系統(tǒng)對抗癌癥作用,。除此之外,，這類藥物還可以對抗其它重要疾病，例如HIV等,。
Shuai的研究小組下一步計劃是研究利用小型化學(xué)分子來作用于PIAS1信號通路,，從而達(dá)到治療癌癥和其它疾病的效果。 （引自教育部科技發(fā)展中心）
英文原文鏈接：http://www.physorg.com/news100527374.html
原始出處:
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
[email protected]
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.
