IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction
5
Citation
35
Reference
10
Related Paper
Citation Trend
Abstract:
The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPR ER ) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPR ER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPR ER activation with age. This underlines the mechanistic difference between age-associated loss of UPR ER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging.Keywords:
Proteostasis
Endoribonuclease
Proteome
Proteostasis
Cite
Citations (23)
Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore proteostasis in the ER. Previously, we demonstrated that UPR activation is an early event in Alzheimer disease (AD) brain. In our recent work we investigated whether activation of the UPR is employed to enhance the capacity of the ubiquitin proteasome system or autophagy in neuronal cells. We showed that the levels, composition and activity of the proteasome are not regulated by the UPR. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain.
Proteostasis
Endoplasmic-reticulum-associated protein degradation
Cite
Citations (90)
Proteostasis
Cite
Citations (75)
The Heat Shock Response (HSR) in the cytosol and the Unfolded Protein Response (UPR) in the endoplasmic reticulum are major pathways of the cellular proteostasis network. In Saccharomyces cerevisiae, HSR is regulated by transcription factor Hsf1, and UPR Ire1 branch activates transcription factor Hac1. Here we demonstrate systemic regulation of proteostasis through a direct link between UPR and HSR. Hsf1 is activated by UPR and its HSR depends on intact UPR. This link is mediated by Sir2, which is not only essential for Hsf1 HSR but also required for Hsf1 activation by UPR. Excess Sir2 augments Hsf1 activation by UPR and can compensate for its impairment in UPR-defective strains. Sir2 is upregulated by UPR but, in turn, it also attenuates this pathway, ensuring that UPR functions only transiently.
HSF1
Proteostasis
XBP1
Heat shock factor
ATF4
Cite
Citations (40)
Proteostasis
XBP1
Cite
Citations (12)
The ability to respond to various intracellular and/or extracellular stresses allows the organism to adapt to changing environmental conditions and drives evolution. It is now well accepted that a progressive decline of the efficiency of stress response pathways occurs with aging. In this context, a correct proteostasis is essential for the functionality of the cell, and its dysfunction has been associated with protein aggregation and age-related degenerative diseases. Complex response mechanisms have evolved to deal with unfolded protein stress in different subcellular compartments and their moderate activation translates into positive effects on health. In this review, we focus on the mitochondrial unfolded protein response (UPRmt), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death. We compare UPRmt with the extensively characterized cytosolic heat shock response (HSR) and the unfolded protein response in endoplasmic reticulum (UPRER), and discuss the current knowledge about UPRmt signaling pathways as well as their potential involvement in physiology.
Cite
Citations (304)
ABSTRACT The PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs ER stress-dependent secretion of destabilized TTR by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition promotes the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization partially restores secretion of native TTR tetramers. However, PERK inhibition still increases the ER stress-dependent secretion of TTR in non-native conformations under these conditions, indicating that the conformation of stable secreted proteins can also be affected by inhibiting PERK. Our results define a role for PERK in regulating extracellular proteostasis during ER stress and indicate that genetic or aging-related alterations in PERK signaling can exacerbate ER stress-related imbalances in extracellular proteostasis implicated in diverse diseases.
Proteostasis
Secretory protein
Cite
Citations (1)
Abstract The PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs secretion of destabilized TTR during thapsigargin (Tg)-induced ER stress by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition increases the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization partially restores secretion of native TTR tetramers. However, PERK inhibition still increases the ER stress-dependent secretion of TTR in non-native conformations under these conditions, indicating that the conformation of stable secreted proteins can also be affected by inhibiting PERK. Our results define a role for PERK in regulating extracellular proteostasis during ER stress and indicate that genetic or aging-related alterations in PERK signaling can exacerbate ER stress-related imbalances in extracellular proteostasis implicated in diverse diseases.
Proteostasis
Secretory protein
Tunicamycin
Thapsigargin
Cite
Citations (23)
Protein unfolding in the endoplasmic reticulum (ER) induces a particular form of proteotoxic cellular stress — ER stress: immature and incorrectly folded proteins can accumulate in the ER lumen and form cytotoxic aggregates. Under ER stress, the non-specific protective mechanism, Unfolded Protein Response (UPR), is activated. The key element of UPR is the signaling pathway mediated by transmembrane ER protein IRE1. The activated endoribonuclease domain IRE1a causes non-canonic XBP1 mRNA splicing, which leads to the synthesis of an active transcription factor sXBP1. It induces the expression of proadaptive genes. In addition to its cytoprotective function, IRE1 is also a key regulator of ER stress-induced cell death. It is assumed that with prolonged activation, IRE1 switches from proadaptive to proapototic regulation. Aim. This paper is devoted to studying possible IRE1a switching from proadaptive to proapoptotic regulation. Using the inhibition of the IRE1a endoribonuclease domain by the compound STF-083010, we analyzed the dependence of cell survival on the period of IRE1a activity under ER stress of varying intensity. We observed the cell specificity of this dependence: in non-secreting Jurkat cells, inhibition of IRE1a in the early stages of intense stress was less toxic than in the later ones; in secreting EA.hy926 cells, an inverse relationship was observed. Purpose of the study. The study of the dependence of cell survival on the duration of the activity of the signaling pathway, mediated by the ribonuclease activity of IRE1, during endoplasmic reticulum stress. Methods. Using RT-qPCR, inhibition of the IRE1α endoribonuclease domain by compound STF-083010, the dependence of cell survival on the period of IRE1α activity during ER stress of various intensities was analyzed. Results. IRE1a exerts a predominantly cytoprotective effect under intense stress — inhibition by the compound STF-083010 reduces cell viability. The character of the dependence of cell survival on the period of IRE1α activity under ER stress is cell-specific: the survival of non-secretive T-lymphoblasts Jurkat was higher when IRE1α was inhibited in the early stages of intense stress than in the latter; for secreting endotheliocyte-like cells EA.hy926, an inverse relationship was observed.
Endoribonuclease
XBP1
Jurkat cells
Tunicamycin
Cite
Citations (0)
The maintenance and regulation of proteostasis is a critical function for post-mitotic neurons and dysregulation of proteostasis is increasingly implicated in neurodegenerative diseases. Despite having different clinical manifestations, these disorders share similar pathology; an accumulation of misfolded proteins in neurons and subsequent disruption to cellular proteostasis. The endoplasmic reticulum (ER) is an important component of proteostasis, and when the accumulation of misfolded proteins occurs within the ER, this disturbs ER homeostasis, giving rise to ER stress. This triggers the unfolded protein response (UPR), distinct signalling pathways that whilst initially protective, are pro-apoptotic if ER stress is prolonged. ER stress is increasingly implicated in neurodegenerative diseases, and emerging evidence highlights the complexity of the UPR in these disorders, with both protective and detrimental components being described. Protein Disulphide Isomerase (PDI) is an ER chaperone induced during ER stress that is responsible for the formation of disulphide bonds in proteins. Whilst initially considered to be protective, recent studies have revealed unconventional roles for PDI in neurodegenerative diseases, distinct from its normal function in the UPR and the ER, although these mechanisms remain poorly defined. However specific aspects of PDI function may offer the potential to be exploited therapeutically in the future. This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.
Proteostasis
Chaperone (clinical)
Cite
Citations (145)