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bioRxiv · 10.1101/2023.04.18.537291

Mild ER Stress Impedes Regulated Secretion By Governing Key Exocytotic and granulogenic Molecular Switches

Sahu, B. S.·Mukherjee, M.·Mukherjee, C.·Ghosh, V.·Jain, A.·sadhukhan, s.·Dagar, s.
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Abstract

Dense core vesicles (DCVs) and synaptic vesicles (SVs) are specialised secretory vesicles (SSVs) in neurons/neuroendocrine cells harbouring cargo whose abnormal release is associated with pathophysiology. Endoplasmic Reticulum (ER) stress and inter-organellar communication are also associated with disease biology. In pursuit of investigating the cell physiological consequences arising from the crosstalk of a stressed ER and DCVs, ER stress was modelled in PC12 neuroendocrine cells using Thapsigargin (Tg). DCV exocytosis was severely compromised in ER-stressed PC12 cells, reversed by Docosahexaenoic acid (DHA). Experiments with Tunicamycin(Tm), an independent ER stressor, yielded similar results. Concurrently, ER stress caused impaired DCV exocytosis also in INS-1 cells. Molecular analysis revealed blunted SNAP25 expression, potentially attributed to augmented levels of ATF4 (a well-known CREB inhibitor) and its transcriptional regulator CREB (also known to regulate key granulogenic players Chromogranin A, Secretogranin II). Our studies revealed severe defects in DCV exocytosis in ER-stressed cells for the first time, mediated by reduced levels of key exocytotic and granulogenic switches regulated via the CREB/ATF4/eIF2 axis.

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Sahu, B. S., Mukherjee, M., Mukherjee, C., Ghosh, V., Jain, A., sadhukhan, s., Dagar, s.. 2023-04-19. Mild ER Stress Impedes Regulated Secretion By Governing Key Exocytotic and granulogenic Molecular Switches. https://doi.org/10.1101/2023.04.18.537291

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