H19 long noncoding RNA controls the mRNA decay promoting function of KSRP.
Long noncoding RNAs (lncRNAs) interact with protein factors to regulate different layers of gene expression transcriptionally or posttranscriptionally. Here we report on the functional consequences of the unanticipated interaction of the RNA binding protein K homology-type splicing regulatory protein (KSRP) with the H19 lncRNA (H19). KSRP directly binds to H19 in the cytoplasm of undifferentiated multipotent mesenchymal C2C12 cells, and this interaction favors KSRP-mediated destabilization of labile transcripts such as myogenin. AKT activation induces KSRP dismissal from H19 and, as a consequence, myogenin mRNA is stabilized while KSRP is repurposed to promote maturation of myogenic microRNAs, thus favoring myogenic differentiation. Our data indicate that H19 operates as a molecular scaffold that facilitates effective association of KSRP with myogenin and other labile transcripts, and we propose that H19 works with KSRP to optimize an AKT-regulated posttranscriptional switch that controls myogenic differentiation.
Gene Expression Regulation Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genoa, Italy;
Matteo
M
Giovarelli
Center for Translational Genomic and Bioinformatics, Ospedale San Raffaele, 20132 Milan, Italy;
Gabriele
G
Bucci
Institute of Structural and Molecular Biology, University College of London, London WC1E 6BT, United Kingdom; Molecular Structure Division, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
Andres
A
Ramos
Gene Expression Regulation Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genoa, Italy;
Domenico
D
Bordo
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523; and.
Carol J
CJ
Wilusz
Department of Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233.
Ching-Yi
CY
Chen
Gene Expression Regulation Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genoa, Italy;
Margherita
M
Puppo
Gene Expression Regulation Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genoa, Italy; paola.briata@hsanmartino.it rgherzi@ucsd.edu.
Paola
P
Briata
Gene Expression Regulation Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genoa, Italy; paola.briata@hsanmartino.it rgherzi@ucsd.edu.
Roberto
R
Gherzi
D000818:Animals; D002460:Cell Line; D006801:Humans; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
C094335:H19 long non-coding RNA; C105789:KHSRP protein, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators
RNA-binding proteins; long noncoding RNA; mRNA decay