Nucleo-cytoplasmic shuttling of Drosophila Hairless/Su(H) heterodimer as a means of regulating Notch dependent transcription
| Autor: | Anette Preiss, Ludmilla Kober, Dieter Maier, Tilman Borggrefe, Mirjam Zimmermann, Thomas K. Smylla, Philipp Hoffmeister, Jan Reichmuth, Anja C. Nagel, Dorina B. Wolf, Franz Oswald, Aleksandra Turkiewicz |
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| Rok vydání: | 2019 |
| Předmět: |
Cytoplasm
animal structures Nuclear Localization Signals Repressor 03 medical and health sciences Transcription (biology) Animals Drosophila Proteins Wings Animal Nuclear export signal Molecular Biology Transcription factor 030304 developmental biology Nuclear Export Signals 0303 health sciences integumentary system Receptors Notch Chemistry RBPJ 030302 biochemistry & molecular biology Wild type Cell Biology Hairless Cell biology Drosophila melanogaster Phenotype Female Nuclear localization sequence Transcription Factors |
| Zdroj: | Biochimica et biophysica acta. Molecular cell research. 1866(10) |
| ISSN: | 1879-2596 |
| Popis: | Activation and repression of Notch target genes is mediated by transcription factor CSL, known as Suppressor of Hairless (Su(H)) in Drosophila and CBF1 or RBPJ in human. CSL associates either with co-activator Notch or with co-repressors such as Drosophila Hairless. The nuclear translocation of transcription factor CSL relies on co-factor association, both in mammals and in Drosophila. The Drosophila CSL orthologue Su(H) requires Hairless for repressor complex formation. Based on its role in transcriptional silencing, H protein would be expected to be strictly nuclear. However, H protein is also cytosolic, which may relate to its role in the stabilization and nuclear translocation of Su(H) protein. Here, we investigate the function of the predicted nuclear localization signals (NLS 1–3) and single nuclear export signal (NES) of co-repressor Hairless using GFP-fusion proteins, reporter assays and in vivo analyses using Hairless wild type and shuttling-defective Hairless mutants. We identify NLS3 and NES to be critical for Hairless function. In fact, H⁎NLS3 mutant flies match H null mutants, whereas H⁎NLS3⁎NES double mutants display weaker phenotypes in agreement with a crucial role for NES in H export. As expected for a transcriptional repressor, Notch target genes are deregulated in H⁎NLS3 mutant cells, demonstrating nuclear requirement for its activity. Importantly, we reveal that Su(H) protein strictly follows Hairless protein localization. Together, we propose that shuttling between the nucleo-cytoplasmic compartments provides the possibility to fine tune the regulation of Notch target gene expression by balancing of Su(H) protein availability for Notch activation. |
| Databáze: | OpenAIRE |
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