AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR.
Nuclear import of HuR, a shuttling RNA-binding protein, is associated with reduced stability of its target mRNAs. Increased function of the AMP-activated protein kinase (AMPK), an enzyme involved in responding to metabolic stress, was recently shown to reduce the cytoplasmic levels of HuR. Here, we provide evidence that importin alpha1, an adaptor protein involved in nuclear import, contributes to the nuclear import of HuR through two AMPK-modulated mechanisms. First, AMPK triggered the acetylation of importin alpha1 on Lys(22), a process dependent on the acetylase activity of p300. Second, AMPK phosphorylated importin alpha1 on Ser(105). Accordingly, expression of importin alpha1 proteins bearing K22R or S105A mutations failed to mediate the nuclear import of HuR in intact cells. Our results point to importin alpha1 as a critical downstream target of AMPK and key mediator of AMPK-triggered HuR nuclear import.
Wang
Wengong
W
Laboratory of Cellular and Molecular Biology, NIA Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
Yang
Xiaoling
X
Kawai
Tomoko
T
López de Silanes
Isabel
I
Mazan-Mamczarz
Krystyna
K
Chen
Peili
P
Chook
Yuh Min
YM
Quensel
Christina
C
Köhler
Matthias
M
Gorospe
Myriam
M
D055372:AMP-Activated Protein Kinases; D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism*; D002460:Cell Line; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004789:Enzyme Activation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D056572:Histone Deacetylase Inhibitors; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D012265:Ribonucleotides; D015534:Trans-Activators; D028901:alpha Karyopherins; C087978:karyopherin alpha 2; D000620:Aminoimidazole Carboxamide; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D006655:Histone Deacetylases; C031143:AICA ribonucleotide; D008239:Lysine