Elements of the UPR pathway are essential to maintaining beta-cell homeostasis under normal conditions, due to the high secretory workload placed on the beta-cell.The endoplasmic reticulum (ER) possesses the structural and functional features expected of an organelle that supports the integration and coordination of major cellular processes. Finally, the induction of AKT1 and reduction of TXNIP serve to inhibit cell death. UPR activation also triggers mRNA decay and attenuates global gene translation to reduce the workload on the ER. When mild or tolerable levels of UPR are activated in beta cells, the UPR transducers PERK, IRE1α, and ATF6 mediate the transcription of genes for chaperones, ERAD components, and autophagy in an attempt to restore ER homeostasis. ATF6f also triggers beta-cell proliferation. ATF6f activates the transcription of genes encoding protein chaperones and ERAD. When ATF6 is released from BiP, it translocates to the Golgi complex, where ATF6 is cleaved to generate ATF6f. In addition, sXbp1 promotes proinsulin folding through various PDI family genes. IRE1α cleaves Xbp1 mRNA, and spliced Xbp1 (sXbp1) mRNA in turn mediates gene transcription of chaperones, lipid synthesis, ERAD, and autophagy. ATF4 mediates the transcription of genes that encode chaperones, oxidoreductases, ERAD, and autophagy. Activated PERK phosphorylates eIF2α, which inhibits global protein translation and activates ATF4. BiP is sequestered by binding to ER-stress inducing unfolded/misfolded protein in the ER lumen, leading to its dissociation from PERK, IRE1α, and ATF6, which are ER membrane-localized stress transducers. UPR activation mediates beta-cell survival. For permissions, please e-mail: Disclaimer Abbreviations: BiP, Binding immunoglobulin Protein ER endoplasmic reticulum ERAD, ER-associated protein degradation IFN, interferon IL, interleukin JNK, c-Jun N-terminal kinase KHE, proton-K+ exchanger MODY, maturity-onset diabetes of young PERK, PRKR-like ER kinase SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases T1D, type 1 diabetes T2D, type 2 diabetes TNF, tumor necrosis factor UPR, unfolded protein response WRS, Wolcott-Rallison syndrome.ĮR stress and ER calcium UPR beta-cell apoptosis type 1 diabetes type 2 diabetes. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. The storage and release of Ca2+ are critical physiological functions of the ER. The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated.
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