TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes.
Although aberrant microRNA (miRNA) expression is linked to human diseases including cancer, the mechanisms that regulate the expression of each individual miRNA remain largely unknown. TAR DNA-binding protein-43 (TDP-43) is homologous to the heterogeneous nuclear ribonucleoproteins (hnRNPs), which are involved in RNA processing, and its abnormal cellular distribution is a key feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases. Here, we show that TDP-43 facilitates the production of a subset of precursor miRNAs (pre-miRNAs) by both interacting with the nuclear Drosha complex and binding directly to the relevant primary miRNAs (pri-miRNAs). Furthermore, cytoplasmic TDP-43, which interacts with the Dicer complex, promotes the processing of some of these pre-miRNAs via binding to their terminal loops. Finally, we show that involvement of TDP-43 in miRNA biogenesis is indispensable for neuronal outgrowth. These results support a previously uncharacterized role for TDP-43 in posttranscriptional regulation of miRNA expression in both the nucleus and the cytoplasm.
Laboratory of RNA Function, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan. ykawahara@rna.med.osaka-u.ac.jp
Yukio
Y
Kawahara
Ai
A
Mieda-Sato
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000378:metabolism*; D046912:Multiprotein Complexes; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000494:pharmacology; D043244:Ribonuclease III / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; D035683:MicroRNAs; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases