Endoplasmic reticulum stress-induced cellular dysfunction and cell death in insulin-producing cells results in diabetes-like phenotypes in Drosophila

Abstract

The destruction of pancreatic β cells leads to reduced insulin secretion and eventually causes diabetes. Various types of cellular stress are thought to be involved in destruction and/or malfunction of these cells. We show that endoplasmic reticulum (ER) stress accumulation in insulin-producing cells (IPCs) generated diabeteslike phenotypes in Drosophila. To promote the accumulation of extra ER stress, we induced a dominant-negative form of a Drosophila ER chaperone protein (Hsc70-3 DN) and demonstrate that it causes the unfolded-protein response (UPR) in various tissues. The numbers of IPCs decreased owing to apoptosis induction mediated by caspases. The apoptosis was driven by activation of Dronc, and subsequently by Drice and Dcp-1. Accordingly, the relative mRNA-expression levels of Drosophila insulin-like peptides significantly decreased. Consistent with these results, we demonstrate that glucose levels in larval haemolymph were significantly higher than those of controls. Accumulation of ER stress induced by continuous Hsc70-3 DN expression in IPCs resulted in the production of undersized flies. Ectopic expression of Hsc70-3 DN can induce more efficient ER stress responses and more severe phenotypes. We propose that ER stress is responsible for IPC loss and dysfunction, which results in diabetes-related pathogenesis in this Drosophila diabetes model. Moreover, inhibiting apoptosis partially prevents the ER stress-induced diabetes-like phenotypes.

Drosophila insulin‐like peptides: from expression to functions – a review

“…Activation of the Drosophila ER chaperone protein Hsc70‐3 DN resulted in a decrease in the number of IPCs due to the induction of apoptosis. It has also been shown that the relative expression levels of dilp2 , dilp3 , and dilp5 are significantly reduced in flies expressing the dominant negative form of Hsc70‐3 (Katsube et al, 2019).…”

Heat shock cognate 70 genes contribute to Drosophila spermatocyte growth progression possibly through the insulin signaling pathway

“…Furthermore, Hsc70‐3 acts as an endoplasmic reticulum (ER) chaperone, similar to its mammalian ortholog, GRP78 (Daugaard et al., 2007). A recent study has revealed that the ectopic expression of a dominant negative form of the protein activates the ER stress‐induced unfolded protein response (Katsube et al., 2019). Such reports strengthen our hypothesis that the cell growth defects of Hsc70‐3‐ silenced spermatocytes might be attributed to the inhibition of protein synthesis due to ER stress.…”

“…In contrast, genes encoding the Hsc70 group of proteins show high levels of expression in both testes and ovaries in Drosophila , suggesting their roles in gametogenesis in Drosophila (see Flybase, http://flybase.org/). These proteins may contribute to the folding of proteins synthesized de novo and maintain the tertiary structures of proteins under conditions of stress (Bukau & Horwich, 1998; Katsube et al., 2019; Ryoo & Steller, 2007). One of the members of the Hsc70 family, Hsc70‐4, is required for the self‐renewal of germline stem cells and differentiation of daughter cells in Drosophila (Yu et al., 2016).…”

The Genetics of Diabetes: What We Can Learn from Drosophila

“…This resulted in increased glucose levels and reduced DILP expression. Using this model, authors demonstrated that diabetes onset might be triggered by a cause–effect relationship between ER stress and induced destruction of IPCs mediated by apoptosis [ 121 ].…”