T cell activation induces proteasomal degradation of argonaute and rapid remodeling of the microRNA repertoire

Yelena Bronevetsky, Alejandro V. Villarino, Christopher J. Eisley, Rebecca Barbeau, Andrea J. Barczak, Gitta A. Heinz, Elisabeth Kremmer, Vigo Heissmeyer, Michael T. McManus, David J. Erle, Anjana Rao, K. Mark Ansel

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

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 cytokineproducing 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.

Original languageEnglish (US)
Pages (from-to)417-432
Number of pages16
JournalJournal of Experimental Medicine
Volume210
Issue number2
DOIs
StatePublished - Feb 2013
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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