The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex.
MicroRNA (miRNA) maturation is regulated by interaction of particular miRNA precursors with specific RNA-binding proteins. Following their biogenesis, mature miRNAs are incorporated into the RNA-induced silencing complex (RISC) where they interact with mRNAs to negatively regulate protein production. However, little is known about how mature miRNAs are regulated at the level of their activity. To address this, we screened for proteins differentially bound to the mature form of the miR-1 or miR-133 miRNA families. These muscle-enriched, co-transcribed miRNA pairs cooperate to suppress smooth muscle gene expression in the heart. However, they also have opposing roles, with the miR-1 family, composed of miR-1 and miR-206, promoting myogenic differentiation, whereas miR-133 maintains the progenitor state. Here, we describe a physical interaction between TDP-43, an RNA-binding protein that forms aggregates in the neuromuscular disease, amyotrophic lateral sclerosis, and the miR-1, but not miR-133, family. Deficiency of the TDP-43 Drosophila ortholog enhanced dmiR-1 activity in vivo. In mammalian cells, TDP-43 limited the activity of both miR-1 and miR-206, but not the miR-133 family, by disrupting their RISC association. Consistent with TDP-43 dampening miR-1/206 activity, protein levels of the miR-1/206 targets, IGF-1 and HDAC4, were elevated in TDP-43 transgenic mouse muscle. This occurred without corresponding Igf-1 or Hdac4 mRNA increases and despite higher miR-1 and miR-206 expression. Our findings reveal that TDP-43 negatively regulates the activity of the miR-1 family of miRNAs by limiting their bioavailability for RISC loading and suggest a processing-independent mechanism for differential regulation of miRNA activity.
From the Gladstone Institute of Cardiovascular Disease and the Departments of Pediatrics.
Isabelle N
IN
King
From the Gladstone Institute of Cardiovascular Disease and.
Valeria
V
Yartseva
From the Gladstone Institute of Cardiovascular Disease and.
Donaldo
D
Salas
From the Gladstone Institute of Cardiovascular Disease and.
Abhishek
A
Kumar
From the Gladstone Institute of Cardiovascular Disease and Biomedical Sciences, Graduate Program, University of California, San Francisco, California 94158, and.
Amy
A
Heidersbach
Biomedical Sciences, Graduate Program, University of California, San Francisco, California 94158, and Gladstone Institute of Neurological Disease, San Francisco, California 94158.
D Michael
DM
Ando
the Department of Neurology and Neurotherapeutics, the University of Texas Southwestern Medical Center, Dallas, Texas 75235.
Nancy R
NR
Stallings
the Department of Neurology and Neurotherapeutics, the University of Texas Southwestern Medical Center, Dallas, Texas 75235.
Jeffrey L
JL
Elliott
From the Gladstone Institute of Cardiovascular Disease and the Departments of Pediatrics, Biochemistry and Biophysics, and.
Deepak
D
Srivastava
From the Gladstone Institute of Cardiovascular Disease and the Departments of Pediatrics, kivey@gladstone.ucsf.edu.
Kathryn N
KN
Ivey
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D011485:Protein Binding; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*
C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D004268:DNA-Binding Proteins; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C540669:Mirn206 microRNA, mouse; D034743:RNA-Induced Silencing Complex
Cardiac muscle; Gene Regulation; MicroRNA; RNA-Protein Interaction; RNA-binding Protein; Skeletal Muscle