title: Novel RNA chaperone domain of RNA-binding protein La is regulated by AKT phosphorylation.
abstract: The cellular function of the cancer-associated RNA-binding protein La has been linked to translation of viral and cellular mRNAs. Recently, we have shown that the human La protein stimulates IRES-mediated translation of the cooperative oncogene CCND1 in cervical cancer cells. However, there is little known about the underlying molecular mechanism by which La stimulates CCND1 IRES-mediated translation, and we propose that its RNA chaperone activity is required. Herein, we show that La binds close to the CCND1 start codon and demonstrate that La's RNA chaperone activity can change the folding of its binding site. We map the RNA chaperone domain (RCD) within the C-terminal region of La in close proximity to a novel AKT phosphorylation site (T389). Phosphorylation at T389 by AKT-1 strongly impairs its RNA chaperone activity. Furthermore, we demonstrate that the RCD as well as T389 is required to stimulate CCND1 IRES-mediated translation in cells. In summary, we provide a model whereby a novel interplay between RNA-binding, RNA chaperoning and AKT phosphorylation of La protein regulates CCND1 IRES-mediated translation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Kuehnert
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Sommer
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Avery W
authors.initials: AW
authors.lastname: Zierk
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Alena
authors.initials: A
authors.lastname: Fedarovich
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brock
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Dzmitry
authors.initials: D
authors.lastname: Fedarovich
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA heise@musc.edu.
authors.forename: Tilman
authors.initials: T
authors.lastname: Heise
mesh_terms: D020121:5' Untranslated Regions; D020816:Amino Acid Motifs; D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D018387:Codon, Initiator; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism; D000097585:SS-B Antigen
chemical_list: D020121:5' Untranslated Regions; D001324:Autoantigens; D018387:Codon, Initiator; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA; D012261:Ribonucleoproteins; D013912:Threonine; D000097585:SS-B Antigen