The RNA-binding protein TDP-43 selectively disrupts MicroRNA-1/206 incorporation into the RNA-induced silencing complex

Isabelle N. King, Valeria Yartseva, Donaldo Salas, Abhishek Kumar, Amy Heidersbach, D. Michael Ando, Nancy R. Stallings, Jeffrey L. Elliott, Deepak Srivastava, Kathryn N. Ivey

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)14263-14271
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number20
DOIs
StatePublished - May 16 2014

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RNA-Induced Silencing Complex
RNA-Binding Proteins
MicroRNAs
Muscle
Muscles
Neuromuscular Diseases
Messenger RNA
Proteins
Insulin-Like Growth Factor I
Gene expression
Transgenic Mice
Biological Availability
Drosophila
Smooth Muscle
Cells
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

King, I. N., Yartseva, V., Salas, D., Kumar, A., Heidersbach, A., Ando, D. M., ... Ivey, K. N. (2014). The RNA-binding protein TDP-43 selectively disrupts MicroRNA-1/206 incorporation into the RNA-induced silencing complex. Journal of Biological Chemistry, 289(20), 14263-14271. https://doi.org/10.1074/jbc.M114.561902

The RNA-binding protein TDP-43 selectively disrupts MicroRNA-1/206 incorporation into the RNA-induced silencing complex. / King, Isabelle N.; Yartseva, Valeria; Salas, Donaldo; Kumar, Abhishek; Heidersbach, Amy; Ando, D. Michael; Stallings, Nancy R.; Elliott, Jeffrey L.; Srivastava, Deepak; Ivey, Kathryn N.

In: Journal of Biological Chemistry, Vol. 289, No. 20, 16.05.2014, p. 14263-14271.

Research output: Contribution to journalArticle

King, IN, Yartseva, V, Salas, D, Kumar, A, Heidersbach, A, Ando, DM, Stallings, NR, Elliott, JL, Srivastava, D & Ivey, KN 2014, 'The RNA-binding protein TDP-43 selectively disrupts MicroRNA-1/206 incorporation into the RNA-induced silencing complex', Journal of Biological Chemistry, vol. 289, no. 20, pp. 14263-14271. https://doi.org/10.1074/jbc.M114.561902
King, Isabelle N. ; Yartseva, Valeria ; Salas, Donaldo ; Kumar, Abhishek ; Heidersbach, Amy ; Ando, D. Michael ; Stallings, Nancy R. ; Elliott, Jeffrey L. ; Srivastava, Deepak ; Ivey, Kathryn N. / The RNA-binding protein TDP-43 selectively disrupts MicroRNA-1/206 incorporation into the RNA-induced silencing complex. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 20. pp. 14263-14271.
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AU - Salas, Donaldo

AU - Kumar, Abhishek

AU - Heidersbach, Amy

AU - Ando, D. Michael

AU - Stallings, Nancy R.

AU - Elliott, Jeffrey L.

AU - Srivastava, Deepak

AU - Ivey, Kathryn N.

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AB - 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.

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