气候变化领域集成服务门户(CCPortal): PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity

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DOI	10.1073/pnas.2010053118
	PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
	Poli A.; Abdul-Hamid S.; Zaurito A.E.; Campagnoli F.; Bevilacqua V.; Sheth B.; Fiume R.; Pagani M.; Abrignani S.; Divecha N.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P2. They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linkedwith susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Immunosuppression; Phosphatidylinositol 5-phosphate 4-kinase; Phosphoinositide kinases; T-regulatory cells; UHRF1
语种	英语
scopus关键词	mammalian target of rapamycin complex 1; mitogen activated protein kinase; peptides and proteins; phosphatidylinositol 3 kinase; phosphatidylinositol 4 phosphate kinase; protein PIP4K2B; protein PIP4K2C; protein UHRF1; S6 kinase; transcription factor FOXP3; unclassified drug; CCAAT enhancer binding protein; forkhead transcription factor; FOXP3 protein, human; mammalian target of rapamycin complex 1; NIH-12848; phosphatidylinositol 3 kinase; phosphotransferase; quinazoline derivative; thiophene derivative; ubiquitin protein ligase; UHRF1 protein, human; Article; cell death; cell survival; controlled study; epigenetics; ex vivo study; helper cell; human; human cell; immune deficiency; lymphocyte proliferation; protein protein interaction; regulatory T lymphocyte; signal transduction; cell proliferation; drug effect; gene expression regulation; genetics; immunology; metabolism; molecular cloning; physiology; regulatory T lymphocyte; CCAAT-Enhancer-Binding Proteins; Cell Proliferation; Cell Survival; Cloning, Molecular; Forkhead Transcription Factors; Gene Expression Regulation, Enzymologic; Humans; Immunosuppression Therapy; Mechanistic Target of Rapamycin Complex 1; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor); Quinazolines; Signal Transduction; T-Lymphocytes, Regulatory; Thiophenes; Ubiquitin-Protein Ligases
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251098
作者单位	Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, 20139, Italy; National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, 20122, Italy; Inositide Laboratory, School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom; Department of Basic Medical Science, Faculty of Nursing, International Islamic University Malaysia, Kuantan, 25200, Malaysia; Center for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany; Department of Experimental Medicine, University of Genova, Genova, 16131, Italy; Department of Biomedical Sciences, University of Bologna, Bologna, 40126, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, 20133, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, 20122, Italy
推荐引用方式 GB/T 7714	Poli A.,Abdul-Hamid S.,Zaurito A.E.,et al. PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity[J],2021,118(31).
APA	Poli A..,Abdul-Hamid S..,Zaurito A.E..,Campagnoli F..,Bevilacqua V..,...&Divecha N..(2021).PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Poli A.,et al."PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).