Here, we investigated transcriptional and trafficking mechanisms of human islet amyloid polypeptide (hIAPP) in normal and stressed β-cells. In high glucose-challenged human islets and rat insulinoma cells overexpressing hIAPP, cell fractionation studies revealed increased accumulation of hIAPP. Unexpectedly, a significant fraction (up to 22%) of hIAPP was found in the nuclear soluble and chromatin-enriched fractions of cultured human islet and rat insulinoma cells. The nucleolar accumulation of monomeric forms of hIAPP did not have any adverse effect on the proliferation of β-cells nor did it affect nucleolar organization or function. However, intact nucleolar organization and function were essential for hIAPP expression under normal and ER-stress conditions as RNA polymerase II inhibitor, α-amanitin, reduced hIAPP protein expression evoked by high glucose and thapsigargin. Promoter activity studies revealed the essential role of transcription factor FoxA2 in hIAPP promoter activation in ER-stressed β-cells. Transcriptome and secretory studies demonstrate that the biosynthetic and secretory capacity of islet β-cells was preserved during ER stress. Thus, the main reason for increased intracellular hIAPP accumulation is its enhanced biosynthesis under these adverse conditions.
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Cover Image
Cover Image
The chart featured in this issue's cover of Biochemical Journal (volume 478, issue 6) depicts a novel non-canonical amylin trafficking pathway to the cell nucleus including its accumulation in an unexpected intracellular compartment, the cell nucleolus. The 3D LSCM micrograph features DAPI-stained nucleus (blue) and amylin assemblies (green) in the two nucleoli (arrowheads). Read more about transcriptional and trafficking mechanisms of human islet amyloid polypeptide in the research piece by Bhowmick et al.
FoxA2 and RNA Pol II mediate human islet amyloid polypeptide turnover in ER-stressed pancreatic β-cells
Diti Chatterjee Bhowmick, Lydia Burnett, Zhanar Kudaibergenova, Aleksandar M. Jeremic; FoxA2 and RNA Pol II mediate human islet amyloid polypeptide turnover in ER-stressed pancreatic β-cells. Biochem J 26 March 2021; 478 (6): 1261–1282. doi: https://doi.org/10.1042/BCJ20200984
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