3′ Uridylation controls mature microRNA turnover during CD4 T-cell activation
- Cristina Gutiérrez-Vázquez1,2,
- Anton J. Enright3,
- Ana Rodríguez-Galán1,2,
- Arantxa Pérez-García2,
- Paul Collier4,
- Matthew R. Jones5,
- Vladimir Benes4,
- Joseph P. Mizgerd5,
- María Mittelbrunn2,
- Almudena R. Ramiro2 and
- Francisco Sánchez-Madrid1,2,6
- 1Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain
- 2Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain
- 3European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
- 4European Molecular Biology Laboratory (EMBL), Core Facilities and Services, Heidelberg 69117, Germany
- 5Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA
- 6CIBER: Centro Investigación en Red Cardiovascular, Madrid 28029, Spain
- Corresponding author: fsmadrid{at}salud.madrid.org
Abstract
Activation of T lymphocytes requires a tight regulation of microRNA (miRNA) expression. Terminal uridyltransferases (TUTases) catalyze 3′ nontemplated nucleotide addition (3′NTA) to miRNAs, which may influence miRNA stability and function. Here, we investigated 3′NTA to mature miRNA in CD4 T lymphocytes by deep sequencing. Upon T-cell activation, miRNA sequences bearing terminal uridines are specifically decreased, concomitantly with down-regulation of TUT4 and TUT7 enzymes. Analyzing TUT4-deficient T lymphocytes, we proved that this terminal uridyltransferase is essential for the maintenance of miRNA uridylation in the steady state of T lymphocytes. Analysis of synthetic uridylated miRNAs shows that 3′ addition of uridine promotes degradation of these uridylated miRNAs after T-cell activation. Our data underline post-transcriptional uridylation as a mechanism to fine-tune miRNA levels during T-cell activation.
Keywords
- 3′ nontemplated nucleotides addition (3′NTA)
- CD4 T lymphocytes
- microRNAs
- uridylation
- Zcchc11 (TUT4)
- Zcchc6 (TUT7)
- isomiRs
Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.060095.116.
- Received November 23, 2016.
- Accepted March 23, 2017.
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