The unfolded protein response and cellular senescence. A Review in the Theme: Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease

Abstract

The endoplasmic reticulum (ER) is a multifunctional organelle critical for the proper folding and assembly of secreted and transmembrane proteins. Perturbations of ER functions cause ER stress, which activates a coordinated system of transcriptional and translational controls called the unfolded protein response (UPR), to cope with accumulation of misfolded proteins and proteotoxicity. It results in ER homeostasis restoration or in cell death. Senescence is a complex cell phenotype induced by several stresses such as telomere attrition, DNA damage, oxidative stress, and activation of some oncogenes. It is mainly characterized by a cell enlargement, a permanent cell-cycle arrest, and the production of a secretome enriched in proinflammatory cytokines and components of the extracellular matrix. Senescent cells accumulate with age in tissues and are suspected to play a role in age-associated diseases. Since senescence is a stress response, the question arises of whether an ER stress could occur concomitantly with senescence and participate in the onset or maintenance of the senescent features. Here, we described the interconnections between the UPR signaling and the different aspects of the cellular senescence programs and discuss the implication of UPR modulations in this context.

Oxidised protein metabolism: recent insights

“…The formation of disulfide bonds in the ER leads to the production of oxidants, inherently linking the ER and oxidative stress (Chakravarthi et al, 2006;Baker et al, 2008;Hudson and Pagliassotti, 2015). Oxidative stress and its corresponding oxidative protein modifications fall under the umbrella term ER stress which can also be caused by mutations, nutrient deprivation or viral infection among other things (Pluquet et al, 2015).…”

Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

“…Many events such as exposure to free radicals and consumption of ER Ca 2+ stores can lead to an unfolded protein response (UPR) and trigger ER stress. 5,6 Although the original activation of the UPR can protect the cell against these adverse situations, sustained or excessive UPR is harmful and contributes to cell apoptosis. 7 Accumulation of unfolded proteins within the ER lumen can simultaneously lead to the overexpression of glucose-regulated protein 78 (GRP78/BiP) and C/EBP homologous protein (CHOP), and activate the caspase-12, a crucial protein related to cell apoptosis induced by ER stress.…”

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

“…It dimerizes and undergoes autophosphorylation upon BiP dissociation and causes the phosphorylation of eukaryotic translation initiation factor 2A (eiF2α) at Ser-51 leading to general translation attenuation, and as a result, induces cell cycle arrest. 7,8 Protein kinase RNA-like endoplasmic reticulum kinase also mediates preferential translation of specific UPR transcripts, such as activating transcription factor 4 (ATF4), and this promotes the transcription of several genes involved in redox response, amino acid synthesis, and lipid biogenesis in an attempt to promote cell survival. Activating transcription factor 4 then activates growth arrest and DNA damage-inducible protein 34, and this dephosphorylates eIF2α which then enables global translation recovery.…”