title: T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire.
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 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.
authors: Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Yelena
authors: Y
authors: Bronevetsky
authors: Alejandro V
authors: AV
authors: Villarino
authors: Christopher J
authors: CJ
authors: Eisley
authors: Rebecca
authors: R
authors: Barbeau
authors: Andrea J
authors: AJ
authors: Barczak
authors: Gitta A
authors: GA
authors: Heinz
authors: Elisabeth
authors: E
authors: Kremmer
authors: Vigo
authors: V
authors: Heissmeyer
authors: Michael T
authors: MT
authors: McManus
authors: David J
authors: DJ
authors: Erle
authors: Anjana
authors: A
authors: Rao
authors: K Mark
authors: KM
authors: Ansel
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D016207:Cytokines; D035683:MicroRNAs; D034743:RNA-Induced Silencing Complex; D046988:Proteasome Endopeptidase Complex
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