title: The Nuclear Zinc Finger Protein Zfat Maintains FoxO1 Protein Levels in Peripheral T Cells by Regulating the Activities of Autophagy and the Akt Signaling Pathway.
abstract: Forkhead box O1 (FoxO1) is a key molecule for the development and functions of peripheral T cells. However, the precise mechanisms regulating FoxO1 expression in peripheral T cells remain elusive. We previously reported that Zfat(f/f)-CD4Cre mice showed a marked decline in FoxO1 protein levels in peripheral T cells, partially through proteasomal degradation. Here we have identified the precise mechanisms, apart from proteasome-mediated degradation, of the decreased FoxO1 levels in Zfat-deficient T cells. First, we confirmed that tamoxifen-inducible deletion of Zfat in Zfat(f/f)-CreERT2 mice coincidently decreases FoxO1 protein levels in peripheral T cells, indicating that Zfat is essential for maintaining FoxO1 levels in these cells. Although the proteasome-specific inhibitors lactacystin and epoxomicin only moderately increase FoxO1 protein levels, the inhibitors of lysosomal proteolysis bafilomycin A1 and chloroquine restore the decreased FoxO1 levels in Zfat-deficient T cells to levels comparable with those in control cells. Furthermore, Zfat-deficient T cells show increased numbers of autophagosomes and decreased levels of p62 protein, together indicating that Zfat deficiency promotes lysosomal FoxO1 degradation through autophagy. In addition, Zfat deficiency increases the phosphorylation levels of Thr-308 and Ser-473 of Akt and the relative amounts of cytoplasmic to nuclear FoxO1 protein levels, indicating that Zfat deficiency causes Akt activation, leading to nuclear exclusion of FoxO1. Our findings have demonstrated a novel role of Zfat in maintaining FoxO1 protein levels in peripheral T cells by regulating the activities of autophagy and the Akt signaling pathway.
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ishikura
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Iwaihara
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Nishi
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and.
authors.forename: Keiko
authors.initials: K
authors.lastname: Doi
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and.
authors.forename: Midori
authors.initials: M
authors.lastname: Koyanagi
authors.affiliation: the Department of Laboratory Animal Medicine and Section of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: From the Department of Cell Biology, Faculty of Medicine and Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan and sshirasa@fukuoka-u.ac.jp.
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D007976:Leupeptins; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D014157:Transcription Factors; C529571:ZFAT protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Akt PKB; FOXO; T cell; Zfat; autophagy; protein degradation