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T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire.
Bronevetsky, Yelena; Villarino, Alejandro V; Eisley, Christopher J; Barbeau, Rebecca; Barczak, Andrea J; Heinz, Gitta A; Kremmer, Elisabeth; Heissmeyer, Vigo; McManus, Michael T; Erle, David J; Rao, Anjana; Ansel, K Mark.
Affiliation
  • Bronevetsky Y; Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
J Exp Med ; 210(2): 417-32, 2013 Feb 11.
Article in En | MEDLINE | ID: mdl-23382546
Activation induces extensive changes in the gene expression program of naive CD4(+) T cells, promoting their differentiation into helper T cells that coordinate immune responses. MicroRNAs (miRNAs) play a critical role in this process, and miRNA expression also changes dramatically during T cell differentiation. Quantitative analyses revealed that T cell activation induces global posttranscriptional miRNA down-regulation in vitro and in vivo. Argonaute (Ago) proteins, the core effector proteins of the miRNA-induced silencing complex (miRISC), were also posttranscriptionally down-regulated during T cell activation. Ago2 was inducibly ubiquitinated in activated T cells and its down-regulation was inhibited by the proteasome inhibitor MG132. Therefore, activation-induced miRNA down-regulation likely occurs at the level of miRISC turnover. Measurements of miRNA-processing intermediates uncovered an additional layer of activation-induced, miRNA-specific transcriptional regulation. Thus, transcriptional and posttranscriptional mechanisms cooperate to rapidly reprogram the miRNA repertoire in differentiating T cells. Altering Ago2 expression in T cells revealed that Ago proteins are limiting factors that determine miRNA abundance. Naive T cells with reduced Ago2 and miRNA expression differentiated more readily into cytokine-producing helper T cells, suggesting that activation-induced miRNA down-regulation promotes acquisition of helper T cell effector functions by relaxing the repression of genes that direct T cell differentiation.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes / MicroRNAs / Argonaute Proteins Limits: Animals / Humans Language: En Journal: J Exp Med Year: 2013 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes / MicroRNAs / Argonaute Proteins Limits: Animals / Humans Language: En Journal: J Exp Med Year: 2013 Document type: Article Affiliation country: Country of publication: