Post-transcriptional fine-tuning of COP9 signalosome subunit biosynthesis is regulated by the c-Myc/Lin28B/let-7 pathway |
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Authors: | Leppert Ulrike Henke Wolfgang Huang Xiaohua Müller Joachim M Dubiel Wolfgang |
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Affiliation: | 1 Department of General, Visceral, Vascular and Thoracic Surgery, Division of Molecular Biology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany2 Department of Otorhinolaryngology, Molecular Biology Research Laboratory, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany3 Department of General, Visceral, Vascular and Thoracic Surgery, Charité - Universitätsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany |
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Abstract: | The COP9 signalosome (CSN) complex controls protein degradation via the ubiquitin (Ub) proteasome system (UPS) in eukaryotes. In mammalian cells, the multimeric CSN is composed of eight subunits (CSN1 - CSN8). It regulates cullin-RING Ub ligases (CRLs), which target essential regulatory proteins for ubiquitination and subsequent degradation. Thereby, the CSN cooperates with the UPS in a variety of essential cellular functions, including DNA repair, cell cycle and differentiation. Although functions of the CSN have been elucidated, mechanisms and regulatory principles of its de novo formation are completely unknown. Here, we show that there is a fundamental mechanism that allows a coordinated expression of all CSN subunits, a prerequisite for CSN assembly. CSN subunit mRNAs are targets of miRNAs of the let-7 family suppressing CSN subunit expression in human cells. Factors that reduce or block let-7 miRNAs induce the coordinated expression of CSN subunits. For instance, over-expression of CSN1 specifically traps let-7a-1 miRNA and elevates CSN subunit levels by two- to fourfold in a coordinated manner. CSN subunit expression is also increased by specific miRNA inhibitors or by interferon (IFN)-mediated induction of STAT1 and c-Myc reducing levels of let-7 miRNAs. Activation of STAT1 by IFNα or IFNγ induces c-Myc, which increases CSN subunit expression via the Lin28B/let-7 regulatory pathway. By contrast, a let-7a-1 mimic reduces CSN subunit expression. Our data show that let-7 miRNAs control the fine-tuning and coordinated expression of subunits for CSN de novo formation, presumably a general regulatory principle for other Zomes complexes as well. |
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Keywords: | CSN, COP9 signalosome eIF, translation initiation complex CRL, cullin-RING ubiquitin ligases Ub, ubiquitin UPS, boldFont" >Ubproteasome system WT, wild type IFN, interferon |
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