Shutdown of Translation: Lethal or Protective? Unfolded Protein Response versus Apoptosis

2003 ◽  
Vol 23 (7) ◽  
pp. 773-779 ◽  
Author(s):  
Wulf Paschen
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Cerebral Ischemia ◽  
Unfolded Protein Response ◽  
Metabolic Stress ◽  
Severe Form ◽  
Transient Cerebral Ischemia ◽  
Stress Genes ◽  
Unfolded Protein ◽  
Protein Response

Shutdown of translation is a highly conserved response of cells to a severe form of metabolic, thermal, or physical stress. After the metabolic stress induced by transient cerebral ischemia, translational recovery is observed only in cells that withstand the transient interruption of blood supply, implying that restoration of translation critically determines the final outcome. On the other hand, apoptosis is believed to play a role in ischemia-induced cell death. Apoptosis is an active process that is blocked by agents known to suppress protein synthesis. Thus, the question arises whether stress-induced suppression of protein synthesis is protective or toxic for the affected cells. Accepting the notion that endoplasmic reticulum (ER) dysfunction is the mechanism underlying shutdown of translation after transient cerebral ischemia, an attempt may be made to try to solve the protein synthesis paradox by understanding the role of protein synthesis suppression in conditions associated with ER dysfunction. Endoplasmic reticulum dysfunction-induced accumulation of unfolded proteins in the ER lumen is the trigger of two signal transduction pathways: PKR-like ER kinase–induced shutdown of translation to suppress new synthesis of proteins that cannot be correctly folded, and IRE1-induced expression of ER stress genes, a protein synthesis–dependent pathway needed to restore ER functions. Together these comprise the unfolded protein response. They are also induced after transient ischemia, implying a dual effect of protein synthesis suppression, a protective and a pathologic effect during early and prolonged reperfusion.

scholarly journals Translational Regulations in Response to Endoplasmic Reticulum Stress in Cancers

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 540 ◽  
Author(s):  
Manon Jaud ◽  
Céline Philippe ◽  
Doriana Di Bella ◽  
Weiwei Tang ◽  
Stéphane Pyronnet ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Translational Control ◽  
Biological Processes ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Wide Range ◽  
Protein Response

During carcinogenesis, almost all the biological processes are modified in one way or another. Among these biological processes affected, anomalies in protein synthesis are common in cancers. Indeed, cancer cells are subjected to a wide range of stresses, which include physical injuries, hypoxia, nutrient starvation, as well as mitotic, oxidative or genotoxic stresses. All of these stresses will cause the accumulation of unfolded proteins in the Endoplasmic Reticulum (ER), which is a major organelle that is involved in protein synthesis, preservation of cellular homeostasis, and adaptation to unfavourable environment. The accumulation of unfolded proteins in the endoplasmic reticulum causes stress triggering an unfolded protein response in order to promote cell survival or to induce apoptosis in case of chronic stress. Transcription and also translational reprogramming are tightly controlled during the unfolded protein response to ensure selective gene expression. The majority of stresses, including ER stress, induce firstly a decrease in global protein synthesis accompanied by the induction of alternative mechanisms for initiating the translation of mRNA, later followed by a translational recovery. After a presentation of ER stress and the UPR response, we will briefly present the different modes of translation initiation, then address the specific translational regulatory mechanisms acting during reticulum stress in cancers and highlight the importance of translational control by ER stress in tumours.

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 Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma

2021 ◽  
Vol 22 (4) ◽  
pp. 1799
Author(s):  
Juncheng Wei ◽  
Deyu Fang
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Response To Treatment ◽  
Protein Accumulation ◽  
Primary Malignancy ◽  
Unfolded Protein ◽  
Protein Response ◽  
Er Homeostasis

Hepatocellular carcinoma (HCC), also known as hepatoma, is a primary malignancy of the liver and the third leading cause of cancer mortality globally. Although much attention has focused on HCC, its pathogenesis remains largely obscure. The endoplasmic reticulum (ER) is a cellular organelle important for regulating protein synthesis, folding, modification and trafficking, and lipid metabolism. ER stress occurs when ER homeostasis is disturbed by numerous environmental, physiological, and pathological challenges. In response to ER stress due to misfolded/unfolded protein accumulation, unfolded protein response (UPR) is activated to maintain ER function for cell survival or, in cases of excessively severe ER stress, initiation of apoptosis. The liver is especially susceptible to ER stress given its protein synthesis and detoxification functions. Experimental data suggest that ER stress and unfolded protein response are involved in HCC development, aggressiveness and response to treatment. Herein, we highlight recent findings and provide an overview of the evidence linking ER stress to the pathogenesis of HCC.

scholarly journals The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane.

1997 ◽  
Vol 8 (9) ◽  
pp. 1805-1814 ◽  
Author(s):  
J S Cox ◽  
R E Chapman ◽  
P Walter
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Lipid Synthesis ◽  
Secretory Proteins ◽  
Endoplasmic Reticulum Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for production of both lumenal and membrane components of secretory pathway compartments. Secretory proteins are folded, processed, and sorted in the ER lumen and lipid synthesis occurs on the ER membrane itself. In the yeast Saccharomyces cerevisiae, synthesis of ER components is highly regulated: the ER-resident proteins by the unfolded protein response and membrane lipid synthesis by the inositol response. We demonstrate that these two responses are intimately linked, forming different branches of the same pathway. Furthermore, we present evidence indicating that this coordinate regulation plays a role in ER biogenesis.

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