title: Karyopherin Alpha 1 Regulates Satellite Cell Proliferation and Survival by Modulating Nuclear Import.
abstract: Satellite cells are stem cells with an essential role in skeletal muscle repair. Precise regulation of gene expression is critical for proper satellite cell quiescence, proliferation, differentiation and self-renewal. Nuclear proteins required for gene expression are dependent on the nucleocytoplasmic transport machinery to access to nucleus, however little is known about regulation of nuclear transport in satellite cells. The best characterized nuclear import pathway is classical nuclear import which depends on a classical nuclear localization signal (cNLS) in a cargo protein and the heterodimeric import receptors, karyopherin alpha (KPNA) and beta (KPNB). Multiple KPNA1 paralogs exist and can differ in importing specific cNLS proteins required for cell differentiation and function. We show that transcripts for six Kpna paralogs underwent distinct changes in mouse satellite cells during muscle regeneration accompanied by changes in cNLS proteins in nuclei. Depletion of KPNA1, the most dramatically altered KPNA, caused satellite cells in uninjured muscle to prematurely activate, proliferate and undergo apoptosis leading to satellite cell exhaustion with age. Increased proliferation of satellite cells led to enhanced muscle regeneration at early stages of regeneration. In addition, we observed impaired nuclear localization of two key KPNA1 cargo proteins: p27, a cyclin-dependent kinase inhibitor associated with cell cycle control and lymphoid enhancer factor 1, a critical cotranscription factor for β-catenin. These results indicate that regulated nuclear import of proteins by KPNA1 is critical for satellite cell proliferation and survival and establish classical nuclear import as a novel regulatory mechanism for controlling satellite cell fate. Stem Cells 2016;34:2784-2797.
authors.affiliation: Department of Pharmacology.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Choo
authors.affiliation: Department of Pharmacology.|Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Cutler
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.|Institute of Biology, University of Lübeck, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Rother
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Department of Pharmacology.
authors.forename: Grace K
authors.initials: GK
authors.lastname: Pavlath
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D017609:Barium Compounds / Q000633:toxicity; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002712:Chlorides / Q000633:toxicity; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D028901:alpha Karyopherins / Q000172:deficiency / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D017609:Barium Compounds; C495267:CTNNB1 protein, mouse; D002712:Chlorides; C527077:KPNA1 protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D019913:Nuclear Localization Signals; D020033:Protein Isoforms; D012333:RNA, Messenger; D028901:alpha Karyopherins; D051176:beta Catenin; C024986:barium chloride; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Importin alpha 5; KPNA1; Karyopherin alpha 1; Nuclear import; Satellite cells; cNLS proteins