Functional proteasome complex is required for turnover of islet amyloid polypeptide in pancreatic β-cells

Abstract

Human islet amyloid polypeptide (hIAPP) is the principal constituent of amyloid deposits and toxic oligomers in the pancreatic islets. Together with hyperglycemia, hIAPP-derived oligomers and aggregates are important culprits in type 2 diabetes mellitus (T2DM). Here, we explored the role of the cell's main proteolytic complex, the proteasome, in hIAPP turnover in normal and stressed β-cells evoked by chronic hyperglycemia. Moderate inhibition (10-35%) of proteasome activity/function in cultured human islets by the proteasome inhibitor lactacystin enhanced intracellular accumulation of hIAPP. Unexpectedly, prolonged (>1 h) and marked (>50%) impairment of proteasome activity/function had a strong inhibitory effect on hIAPP transcription and secretion from normal and stressed β-cells. This negative compensatory feedback mechanism for controlling IAPP turnover was also observed in the lactacystin-treated rat insulinoma β-cell line (INS 832/13), demonstrating the presence of an evolutionarily conserved mechanism for IAPP production. In line with these studies, our current data showed that proteasome activity and hIAPP expression are also down-regulated in islets isolated from T2DM subjects. Gene expression and promoter activity studies demonstrated that the functional proteasome complex is required for efficient activation of the promoter and for full expression of 's essential transcription factor, FOXA2. ChIP studies revealed that promoter occupancy of FoxA2 at the rat promoter region is an important and limiting factor for amylin expression in proteasome-impaired murine cells. This study suggests a novel regulatory pathway in β-cells involving proteasome, FOXA2, and , which can be possibly targeted to regulate hIAPP levels and islet amyloidosis in T2DM.

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

“…Recent papers have evidenced that 20S proteasome activation may protect cells from amyloid proteotoxic stress. [53,54] Accumulating evidence suggests that a deranged equilibrium between production and clearance of the amyloid Aβ peptide -which plays a pivotal role in AD pathogenesis -could result from a declined proteasome activity. Based on this hypothesis, an increasingly large number of reports focuses on the possibility to modulate proteasome activity by drug treatment.…”

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

“…The authors showed that the altered protein-lipid composition of the EVs is the main reason for this discrepancy ( 95 ). However, Chatterjee et al have shown that β-cells from T2DM patients have a dysfunctional proteasome complex that fails to degrade pancreatic IAPP, whereby amyloid formation is induced ( 96 ). Furthermore, in T2DM patients, lipids accelerate the formation of fibrillary IAPP, which aggravates islet cell damage ( 97 ).…”

Anti-IAPP Monoclonal Antibody Improves Clinical Symptoms in a Mouse Model of Type 2 Diabetes

“…Aggregated IAPP have cytotoxic properties [24,25] and their presence is associated with β-cell failure, loss of β-cells, and correlates with severity of T2DM in affected patients [15,26,27]. Recently, it has been demonstrated that impaired intracellular turnover of IAPP by proteasomes and autophagy contribute to the accumulation of toxic IAPP, leading to β-cell death during T2DM [28,29]. Therefore, effective therapeutic strategies for disease modifying treatment of T2DM are urgently needed.…”