The maintenance of homeostasis by cells and organisms under stressful conditions is achieved through the activation of a highly conserved cellular stress response. Adaptive stress responses respond to stimuli and restore cellular homeostasis through a network of signaling mechanisms, but sustained and/or excessive stress responses can be harmful and even lead to apoptosis. Cellular stress usually affects multiple organelles simultaneously, triggering multiple stress responses. It's likely that the interactions, co-regulation, and non-cell-autonomous effects of these stress responses are very important in determining whether a response is adaptive or non-adaptive, but we still don't fully understand how these interactions work.
Endoplasmic reticulum (ER) stress is a type of cellular stress caused by the accumulation of unfolded proteins in the ER, viral infections, toxins, and chronic inflammation. ER stress triggers an unfolded protein response (UPR) to relieve stress and restore intracellular homeostasis. The The classical UPR is mediated by the activation of IRE1 (inositol-requiring protein-1), which is localized in the endoplasmic reticulum membrane, protein kinase RNA-like ER kinase (PERK), and activator of transcription-6 (ATF6), among others. PERK reduces most of the mRNA translation but can be specifically activated by PERK. PERK reduces the translation of most mRNAs but specifically induces the translation of the transcription factor Atf4, which regulates amino acid metabolism and the expression of genes related to oxidative stress reduction. Activation of IRE1a induces highly specific splicing of XBP1 mRNA, resulting in the production of spliced XBP1, a transcription factor regulating UPR target genes, which then regulates the expression of endoplasmic reticulum (ER)-associated protein degradation (ERAD) components and lipid biosynthesis enzyme transcription. ATF6 undergoes proteolytic cleavage in the Golgi and acts as an active transcription factor to up-regulate target genes encoding the ER molecule-associated degradation component, the ERAD component, and XBP1. Although the UPR initially attempts to promote cellular adaptation to ER stress, under sustained or severe stress, it induces a pro-apoptotic response that removes cells from the terminally stressed state.
Type 1 diabetes (T1D) pathogenesis is triggered by the initiation of an autoimmune process that results in almost complete death of pancreatic β-cells, leading to insulin deficiency. The important function of pancreatic β-cells in the initiation of their autoimmunity and the impact of aberrant stress responses on the disease progression of T1D have attracted considerable academic attention over the