FoxA2 and RNA Pol II mediate human islet amyloid polypeptide turnover in ER-stressed pancreatic β-cells.

Abstract

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.

• Authors: Diti Chatterjee Bhowmick, Lydia Burnett, Zhanar Kudaibergenova, Aleksandar M Jeremic
• Journal: The Biochemical journal (Biochem J) Vol. 478 Issue 6 Pg. 1261-1282 (03 26 2021) ISSN: 1470-8728 [Electronic] England
• PMID: 33650632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• FOXA2 protein, human
• Islet Amyloid Polypeptide
• Sweetening Agents
• Hepatocyte Nuclear Factor 3-beta
• RNA Polymerase II
• Glucose

Topics

• Animals
• Cell Proliferation
• Cells, Cultured
• Endoplasmic Reticulum Stress
• Gene Expression Regulation
• Glucose (pharmacology)
• Hepatocyte Nuclear Factor 3-beta (genetics, metabolism)
• Humans
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Islet Amyloid Polypeptide (genetics, metabolism)
• RNA Polymerase II (genetics, metabolism)
• Rats
• Sweetening Agents