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Bronevetsky, Y.* ; Villarino, A.V.* ; Eisley, C.J.* ; Barbeau, R.* ; Barczak, A.J.* ; Heinz, G.A. ; Kremmer, E. ; Heissmeyer, V. ; McManus, M.T.* ; Erle, D.J.* ; Rao, A.* ; Ansel, K.M.*

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

J. Exp. Med. 210, 417-432 (2013)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Posttranscriptional Regulation ; Transcription Factors ; Immune-responses ; Ubiquitin Ligase ; Gene-expression ; Rna-binding ; Differentiation ; Biogenesis ; Proteins ; Pathway
ISSN (print) / ISBN 0022-1007
e-ISSN 1540-9538
Journal Journal of Experimental Medicine
Quellenangaben Volume: 210, Issue: 2, Pages: 417-432 Article Number: , Supplement: ,
Publisher Rockefeller University Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
Research Unit Molecular Immune Regulation (AMIR)