scholarly journals Transient arrest in proteasomal degradation during inhibition of translation in the unfolded protein response

2007 ◽  
Vol 404 (3) ◽  
pp. 509-516 ◽  
Author(s):  
Marina Shenkman ◽  
Sandra Tolchinsky ◽  
Maria Kondratyev ◽  
Gerardo Z. Lederkremer
Keyword(s):  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Proteasomal Degradation ◽  
Protein Synthesis Inhibitors ◽  
Translation Arrest ◽  
Unfolded Protein ◽  
Cycle Arrest ◽  
Translation Block ◽  
The Unfolded Protein Response ◽  
Protein Response

The UPR (unfolded protein response) activates transcription of genes involved in proteasomal degradation. However, we found that in its early stages the UPR leads to a transient inhibition of proteasomal disposal of cytosolic substrates (p53 and p27kip1) and of those targeted to ER (endoplasmic reticulum)-associated degradation (uncleaved precursor of asialoglycoprotein receptor H2a). Degradation resumed soon after the protein synthesis arrest that occurs in early UPR subsided. Consistent with this, protein synthesis inhibitors blocked ubiquitin/proteasomal degradation. Ubiquitination was inhibited during the translation block, suggesting short-lived E3 ubiquitin ligases as candidate depleted proteins. This was indeed the case for p53 whose E3 ligase, Mdm2 (murine double minute 2), when overexpressed, restored the degradation, whereas a mutant Mdm2 in its acidic domain restored the ubiquitination but did not completely restore the degradation. Inhibition of proteasomal degradation early in UPR may prevent depletion of essential short-lived factors during the translation arrest. Stabilization of p27 through this mechanism may explain the cell cycle arrest in G1 when translation is blocked by inhibitors or by the UPR.

scholarly journals Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response

2016 ◽  
Vol 36 (13) ◽  
pp. 1868-1880 ◽  
Author(s):  
David W. Reid ◽  
Angeline S. L. Tay ◽  
Jeyapriya R. Sundaram ◽  
Irene C. J. Lee ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Control Cell ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Current View ◽  
Eukaryotic Initiation Factor ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation in stressed cells. While phosphorylated eIF2α (P-eIF2α) attenuates global protein synthesis, mRNAs encoding stress proteins are more efficiently translated. Two eIF2α phosphatases, containing GADD34 and CReP, catalyze P-eIF2α dephosphorylation. The current view of GADD34, whose transcription is stress induced, is that it functions in a feedback loop to resolve cell stress. In contrast, CReP, which is constitutively expressed, controls basal P-eIF2α levels in unstressed cells. Our studies show that GADD34 drives substantial changes in mRNA translation in unstressed cells, particularly targeting the secretome. Following activation of the unfolded protein response (UPR), rapid translation ofGADD34mRNA occurs and GADD34 is essential for UPR progression. In the absence of GADD34, eIF2α phosphorylation is persistently enhanced and the UPR translational program is significantly attenuated. This “stalled” UPR is relieved by the subsequent activation of compensatory mechanisms that include AKT-mediated suppression of PKR-like kinase (PERK) and increased expression ofCRePmRNA, partially restoring protein synthesis. Our studies highlight the coordinate regulation of UPR by the GADD34- and CReP-containing eIF2α phosphatases to control cell viability.

The unfolded protein response is triggered following a single, unaccustomed resistance-exercise bout

2014 ◽  
Vol 307 (6) ◽  
pp. R664-R669 ◽  
Author(s):  
Daniel I. Ogborn ◽  
Bryon R. McKay ◽  
Justin D. Crane ◽  
Gianni Parise ◽  
Mark A. Tarnopolsky
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Resistance Exercise ◽  
Unfolded Protein Response ◽  
Initiation Factor ◽  
Knee Extensors ◽  
Leg Extension ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress results from an imbalance between the abundance of synthesized proteins and the folding capacity of the ER. In response, the unfolded protein response (UPR) attempts to restore ER function by attenuating protein synthesis and inducing chaperone expression. Resistance exercise (RE) stimulates protein synthesis; however, a postexercise accumulation of unfolded proteins may activate the UPR. Aging may impair protein folding, and the accumulation of oxidized and misfolded proteins may stimulate the UPR at rest in aged muscle. Eighteen younger ( n = 9; 21 ± 3 yr) and older ( n = 9; 70 ± 4 yr) untrained men completed a single, unilateral bout of RE using the knee extensors (four sets of 10 repetitions at 75% of one repetition maximum on the leg press and leg extension) to determine whether the UPR is increased in resting, aged muscle and whether RE stimulates the UPR. Muscle biopsies were taken from the nonexercised and exercised vastus lateralis at 3, 24, and 48 h postexercise. Age did not affect any of the proteins and transcripts related to the UPR. Glucose-regulated protein 78 (GRP78) and protein kinase R-like ER protein kinase (PERK) proteins were increased at 48 h postexercise, whereas inositol-requiring enzyme 1 alpha (IRE1α) was elevated at 24 h and 48 h. Despite elevated protein, GRP78 and PERK mRNA was unchanged; however, IRE1α mRNA was increased at 24 h postexercise. Activating transcription factor 6 (ATF6) mRNA increased at 24 h and 48 h, whereas ATF4, CCAAT/enhancer-binding protein homologous protein (CHOP), and growth arrest and DNA damage protein 34 mRNA were unchanged. These data suggest that RE activates specific pathways of the UPR (ATF6/IRE1α), whereas PERK/eukaryotic initiation factor 2 alpha/CHOP does not. In conclusion, acute RE results in UPR activation, irrespective of age.

scholarly journals MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

2016 ◽  
Vol 36 (23) ◽  
pp. 2931-2944 ◽  
Author(s):  
David A. Hess ◽  
Katherine M. Strelau ◽  
Anju Karki ◽  
Mei Jiang ◽  
Ana C. Azevedo-Pouly ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Cell ◽  
Transcriptional Networks ◽  
Binding Studies ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 ( Bhlha15 ), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

scholarly journals Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

2015 ◽  
Vol 112 (15) ◽  
pp. 4737-4742 ◽  
Author(s):  
Neal D. Andruska ◽  
Xiaobin Zheng ◽  
Xujuan Yang ◽  
Chengjian Mao ◽  
Mathew M. Cherian ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Tumor Regression ◽  
Estrogen Receptor Α ◽  
Unfolded Protein ◽  
Inhibition Of Protein Synthesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen–ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen–ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα+ cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca2+ levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI’s novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.

Cell cycle arrest mediated by WEE1 is involved in the unfolded protein response in plants

2018 ◽  
Vol 12 (5) ◽  
pp. 315-328
Author(s):  
Ki Seong Ko ◽  
Jae Yong Yoo ◽  
Nirmal Kumar Ramasamy ◽  
Rikno Harmoko ◽  
Bích Ngọc Thị Vũ ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Cycle Arrest ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Stable Ribosome Binding to the Endoplasmic Reticulum Enables Compartment-specific Regulation of mRNA Translation

2005 ◽  
Vol 16 (12) ◽  
pp. 5819-5831 ◽  
Author(s):  
Samuel B. Stephens ◽  
Rebecca D. Dodd ◽  
Joseph W. Brewer ◽  
Patrick J. Lager ◽  
Jack D. Keene ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Stress Proteins ◽  
Signal Sequence ◽  
Mrna Translation ◽  
Physiological Basis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

In eukaryotic cells, protein synthesis is compartmentalized; mRNAs encoding secretory/membrane proteins are translated on endoplasmic reticulum (ER)-bound ribosomes, whereas mRNAs encoding cytosolic proteins are translated on free ribosomes. mRNA partitioning between the two compartments occurs via positive selection: free ribosomes engaged in the translation of signal sequence-encoding mRNAs are trafficked from the cytosol to the ER. After translation termination, ER-bound ribosomes are thought to dissociate, thereby completing a cycle of mRNA partitioning. At present, the physiological basis for termination-coupled ribosome release is unknown. To gain insight into this process, we examined ribosome and mRNA partitioning during the unfolded protein response, key elements of which include suppression of the initiation stage of protein synthesis and polyribosome breakdown. We report that unfolded protein response (UPR)-elicited polyribosome breakdown resulted in the continued association, rather than release, of ER-bound ribosomes. Under these conditions, mRNA translation in the cytosol was suppressed, whereas mRNA translation on the ER was sustained. Furthermore, mRNAs encoding key soluble stress proteins (XBP-1 and ATF-4) were translated primarily on ER-bound ribosomes. These studies demonstrate that ribosome release from the ER is termination independent and identify new and unexpected roles for the ER compartment in the translational response to induction of the unfolded protein response.

scholarly journals PERK (Protein Kinase RNA-Like ER Kinase) Branch of the Unfolded Protein Response Confers Neuroprotection in Ischemic Stroke by Suppressing Protein Synthesis

Stroke ◽  
2020 ◽  
Vol 51 (5) ◽  
pp. 1570-1577 ◽  
Author(s):  
Ya-chao Wang ◽  
Xuan Li ◽  
Yuntian Shen ◽  
Jingjun Lyu ◽  
Huaxin Sheng ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Artery Occlusion ◽  
Stroke Outcome ◽  
Stroke Outcomes ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cerebral Artery Occlusion ◽  
Ischemic Stress

Background and Purpose— Ischemic stroke impairs endoplasmic reticulum (ER) function, causes ER stress, and activates the unfolded protein response. The unfolded protein response consists of 3 branches controlled by ER stress sensor proteins, which include PERK (protein kinase RNA-like ER kinase). Activated PERK phosphorylates eIF2α (eukaryotic initiation factor 2 alpha), resulting in inhibition of global protein synthesis. Here, we aimed to clarify the role of the PERK unfolded protein response branch in stroke. Methods— Neuron-specific and tamoxifen-inducible PERK conditional knockout (cKO) mice were generated by cross-breeding Camk2a-CreERT2 with Perk f/f mice. Transient middle cerebral artery occlusion was used to induce stroke. Short- and long-term stroke outcomes were evaluated. Protein synthesis in the brain was assessed using a surface-sensing-of-translation approach. Results— After tamoxifen-induced deletion of Perk in forebrain neurons was confirmed in PERK-cKO mice, PERK-cKO and control mice were subjected to transient middle cerebral artery occlusion and 3 days or 3 weeks recovery. PERK-cKO mice had larger infarcts and worse neurological outcomes compared with control mice, suggesting that PERK-induced eIF2α phosphorylation and subsequent suppression of translation protects neurons from ischemic stress. Indeed, better stroke outcomes were observed in PERK-cKO mice that received postischemic treatment with salubrinal, which can restore the ischemia-induced increase in phosphorylated eIF2α in these mice. Finally, our data showed that post-treatment with salubrinal improved functional recovery after stroke. Conclusions— Here, we presented the first evidence that postischemic suppression of translation induced by PERK activation promotes recovery of neurological function after stroke. This confirms and further extends our previous observations that recovery of ER function impaired by ischemic stress critically contributes to stroke outcome. Therefore, future research should include strategies to improve stroke outcome by targeting unfolded protein response branches to restore protein homeostasis in neurons.

scholarly journals Ribosomal Stress Couples the Unfolded Protein Response to p53-dependent Cell Cycle Arrest

2006 ◽  
Vol 281 (40) ◽  
pp. 30036-30045 ◽  
Author(s):  
Fang Zhang ◽  
Robert B. Hamanaka ◽  
Ekaterina Bobrovnikova-Marjon ◽  
John D. Gordan ◽  
Mu-Shui Dai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Cycle Arrest ◽  
Dependent Cell ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Ribosomal Stress

Oestrogen-driven changes in the bovine uterus are associated with activation of the unfolded protein response

2014 ◽  
Author(s):  
Mohammed A Alfattah ◽  
Paul Anthony McGettigan ◽  
John Arthur Browne ◽  
Khalid M Alkhodair ◽  
Katarzyna Pluta ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
Sign in / Sign up

Export Citation Format

Share Document