BBS4 Is Essential for Nuclear Transport of Transcription Factors Mediating Neuronal ER Stress Response
Autor: | Avital Horwitz, Ruth Birk |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
P50 Neuroscience (miscellaneous) Apoptosis Biology Models Biological 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Humans Gene silencing RNA Messenger Phosphorylation RNA Small Interfering Transcription factor Cell Nucleus Neurons Tunicamycin Endoplasmic reticulum Cell Differentiation Endoplasmic Reticulum Stress Activating Transcription Factor 6 Cell biology Protein Transport 030104 developmental biology Neurology Unfolded Protein Response Unfolded protein response Microtubule-Associated Proteins Neural development Biomarkers 030217 neurology & neurosurgery Transcription Factors |
Zdroj: | Molecular Neurobiology. 58:78-91 |
ISSN: | 1559-1182 0893-7648 |
Popis: | Bardet-Biedl syndrome (BBS) is an autosomal recessive syndrome presenting with retinal dystrophy, cognitive impairment, and obesity. BBS is characterized by elevated endoplasmic reticulum (ER) stress in the early stages of adipocyte and retinal development. BBS expression in the CNS and indications of hippocampal dysgenesis suggest neural development abnormalities. However, the role of BBS in ER stress in neuronal cells has not yet been studied. Therefore, we aimed at studying the role of BBS4 in neuronal development under normal and ER stress conditions. ER stress and unfolded protein response (UPR) were studied in BBS4-silenced (SiBBS4) SH-SY5Y cells during differentiation under normal and stress states, using molecular and biochemical markers. ER stress was demonstrated at early neural differentiation, with significantly augmented expression of UPR markers corresponding to BBS4 expression. In the undifferentiated state, BBS4 silencing resulted in significantly reduced ER-stress markers' expression under normal and ER-stress states. Independent of ER stress, SiBBS4 cells demonstrated significant reduction in activated phospho-IRE1α. Under BBS4 silencing, both sXBP-1 and activated ATF6α p50 failed to translocate to the nucleus. Transcript levels of apoptosis markers were upregulated under BBS4 depletion and ER-stress induction, corresponding to decreased viability. BBS4 depletion in neuronal cells results in reduced sensitivity to ER stress during differentiation and under ER-stress induction, partly due to failure in translocation of ER-transcription factors (TF) sXBP-1 and ATF6α p50 to the nucleus. Hence, BBS4 is essential for nuclear transport under ER-stress response in neuronal cells during early differentiation. Our studies shed light on molecular mechanisms through which BBS4 malfunction alters neuronal ER stress response. |
Databáze: | OpenAIRE |
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