scholarly journals UPRER promotes lipophagy independent of chaperones to extend life span

2020 ◽  
Vol 6 (1) ◽  
pp. eaaz1441 ◽  
Author(s):  
Joseph R. Daniele ◽  
Ryo Higuchi-Sanabria ◽  
Jenni Durieux ◽  
Samira Monshietehadi ◽  
Vidhya Ramachandran ◽  
...  
Keyword(s):  
Life Span ◽  
Genetic Factors ◽  
Protein Homeostasis ◽  
Life Span Extension ◽  
Unfolded Protein ◽  
Extend Life Span ◽  
Protein Chaperones ◽  
Ectopic Activation ◽  
The Unfolded Protein Response ◽  
Protein Response

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms to regulate life-span extension is the induction of protein chaperones for protein homeostasis. Ectopic activation of the unfolded protein response of the endoplasmic reticulum (UPRER) specifically in neurons is sufficient to enhance organismal stress resistance and extend life span. Here, we find that this activation not only promotes chaperones but also facilitates ER restructuring and ER function. This restructuring is concomitant with lipid depletion through lipophagy. Activation of lipophagy is distinct from chaperone induction and is required for the life-span extension found in this paradigm. Last, we find that overexpression of the lipophagy component, ehbp-1, is sufficient to deplete lipids, remodel ER, and promote life span. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the proteostasis arm through protein chaperones and metabolic changes through lipid depletion mediated by EH domain binding protein 1 (EHBP-1).

scholarly journals A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy

2018 ◽  
Author(s):  
Joseph R. Daniele ◽  
Ryo Higuchi-Sanabria ◽  
Vidhya Ramachandran ◽  
Melissa Sanchez ◽  
Jenni Durieux ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Genetic Factors ◽  
Lifespan Extension ◽  
Protein Homeostasis ◽  
Peripheral Tissues ◽  
Unfolded Protein ◽  
Chaperone Function ◽  
Protein Chaperones ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACTLongevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms implicated in regulating lifespan extension is the ability to induce protein chaperones to promote protein homeostasis. However, it is unclear whether protein chaperones exclusively regulate longevity. Previous work has shown that activating the unfolded protein response of the endoplasmic reticulum (UPRER) in neurons can signal peripheral tissues to promote chaperone expression, thus enhancing organismal stress resistance and extending lifespan. Here, we find that this activation not only promotes chaperones, but facilitates a dramatic restructuring of ER morphology in intestinal cells. This restructuring, which includes depletion of lipid droplets, ER expansion, and ER tubulation, depends of lipophagy. Surprisingly, we find that lipophagy is required for lifespan extension and is completely independent of chaperone function. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the canonical arm through protein chaperones, and a non-canonical mechanism through lipid depletion. In summary, our study identifies lipophagy as an integral component of UPRER-induced longevity.

scholarly journals Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans

Science ◽  
2020 ◽  
Vol 367 (6476) ◽  
pp. 436-440 ◽  
Author(s):  
Ashley E. Frakes ◽  
Melissa G. Metcalf ◽  
Sarah U. Tronnes ◽  
Raz Bar-Ziv ◽  
Jenni Durieux ◽  
...  
Keyword(s):  
Er Stress ◽  
Life Span ◽  
Glial Cells ◽  
Stress Responses ◽  
Stress Resistance ◽  
Life Span Extension ◽  
C Elegans ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The ability of the nervous system to sense cellular stress and coordinate protein homeostasis is essential for organismal health. Unfortunately, stress responses that mitigate disturbances in proteostasis, such as the unfolded protein response of the endoplasmic reticulum (UPRER), become defunct with age. In this work, we expressed the constitutively active UPRER transcription factor, XBP-1s, in a subset of astrocyte-like glia, which extended the life span in Caenorhabditis elegans. Glial XBP-1s initiated a robust cell nonautonomous activation of the UPRER in distal cells and rendered animals more resistant to protein aggregation and chronic ER stress. Mutants deficient in neuropeptide processing and secretion suppressed glial cell nonautonomous induction of the UPRER and life-span extension. Thus, astrocyte-like glial cells play a role in regulating organismal ER stress resistance and longevity.

scholarly journals ER stress causes widespread protein aggregation and prion formation

2017 ◽  
Vol 216 (8) ◽  
pp. 2295-2304 ◽  
Author(s):  
Norfadilah Hamdan ◽  
Paraskevi Kritsiligkou ◽  
Chris M. Grant
Keyword(s):  
Protein Aggregation ◽  
Er Stress ◽  
Secretory Pathway ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

scholarly journals ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Richard H Chapple ◽  
Tianyuan Hu ◽  
Yu-Jung Tseng ◽  
Lu Liu ◽  
Ayumi Kitano ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Estrogen Receptor Α ◽  
Protein Homeostasis ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Systemic Mechanism ◽  
Unfolded Protein ◽  
Proteotoxic Stress ◽  
The Unfolded Protein Response ◽  
Protein Response

Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration.

scholarly journals The Unfolded Protein Response: An Overview

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 384
Author(s):  
Adam Read ◽  
Martin Schröder
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Unfolded Protein Response ◽  
Protein Homeostasis ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Altered Glycosylation ◽  
Stressed Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.

scholarly journals How to design an optimal sensor network for the unfolded protein response

2018 ◽  
Vol 29 (25) ◽  
pp. 3052-3062 ◽  
Author(s):  
Wylie Stroberg ◽  
Hadar Aktin ◽  
Yonatan Savir ◽  
Santiago Schnell
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cellular Protein ◽  
Protein Accumulation ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
Stress Sensing ◽  
Coarse Model ◽  
The Unfolded Protein Response ◽  
Protein Response

Cellular protein homeostasis requires continuous monitoring of stress in the endoplasmic reticulum (ER). Stress-detection networks control protein homeostasis by mitigating the deleterious effects of protein accumulation, such as aggregation and misfolding, with precise modulation of chaperone production. Here, we develop a coarse model of the unfolded protein response in yeast and use multi-objective optimization to determine which sensing and activation strategies optimally balance the trade-off between unfolded protein accumulation and chaperone production. By comparing a stress-sensing mechanism that responds directly to the level of unfolded protein in the ER to a mechanism that is negatively regulated by unbound chaperones, we show that chaperone-mediated sensors are more efficient than sensors that detect unfolded proteins directly. This results from the chaperone-mediated sensor having separate thresholds for activation and deactivation. Finally, we demonstrate that a sensor responsive to both unfolded protein and unbound chaperone does not further optimize homeostatic control. Our results suggest a strategy for designing stress sensors and may explain why BiP-mitigated ER stress-sensing networks have evolved.

scholarly journals The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins

2021 ◽  
Author(s):  
Katharina Knoeringer ◽  
Carina Groh ◽  
Lena Kraemer ◽  
Kevin C Stein ◽  
Katja G Hansen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Unfolded Protein Response ◽  
Mitochondrial Membrane ◽  
Cellular Protein ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of non-imported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPR-ER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The levels of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPR-ER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.

scholarly journals Unfolded Protein Response Suppression in Yeast by Loss of tRNA Modifications

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 516 ◽  
Author(s):  
Alexander Bruch ◽  
Roland Klassen ◽  
Raffael Schaffrath
Keyword(s):  
Unfolded Protein Response ◽  
Protein Homeostasis ◽  
Anticodon Loop ◽  
Transfer Rnas ◽  
Unfolded Protein ◽  
Optimal Codon ◽  
Trna Species ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Yeast Mutants

Modifications in the anticodon loop of transfer RNAs (tRNAs) have been shown to ensure optimal codon translation rates and prevent protein homeostasis defects that arise in response to translational pausing. Consequently, several yeast mutants lacking important anticodon loop modifications were shown to accumulate protein aggregates. Here we analyze whether this includes the activation of the unfolded protein response (UPR), which is commonly triggered by protein aggregation within the endoplasmic reticulum (ER). We demonstrate that two different aggregation prone tRNA modification mutants (elp6 ncs2; elp3 deg1) lacking combinations of 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U: elp3; elp6; ncs2) and pseudouridine (Ψ: deg1) reduce, rather than increase, splicing of HAC1 mRNA, an event normally occurring as a precondition of UPR induction. In addition, tunicamycin (TM) induced HAC1 splicing is strongly impaired in the elp3 deg1 mutant. Strikingly, this mutant displays UPR independent resistance against TM, a phenotype we found to be rescued by overexpression of tRNAGln(UUG), the tRNA species usually carrying the mcm5s2U34 and Ψ38 modifications. Our data indicate that proper tRNA anticodon loop modifications promote rather than impair UPR activation and reveal that protein synthesis and homeostasis defects in their absence do not routinely result in UPR induction but may relieve endogenous ER stress.

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