scholarly journals Lysosomal recycling of amino acids affects ER quality control

2020 ◽  
Vol 6 (26) ◽  
pp. eaaz9805
Author(s):  
Ryo Higuchi-Sanabria ◽  
Koning Shen ◽  
Naame Kelet ◽  
Phillip A. Frankino ◽  
Jenni Durieux ◽  
...  
Keyword(s):  
Amino Acids ◽  
Quality Control ◽  
Er Stress ◽  
Building Blocks ◽  
Stress Sensitivity ◽  
Loss Of Function ◽  
Er Quality Control ◽  
Glycine Metabolism ◽  
Increased Sensitivity ◽  
Cellular Compartments

Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPRER. Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1–dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in laat-1 mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.

ER Quality Control and ER Stress-induced Cell Death in Neurodegenerative Diseases

2007 ◽  
Vol 49 (1) ◽  
pp. 39-46
Author(s):  
Atsushi Nagai ◽  
Hisae Kadowaki ◽  
Hideki Nishitoh
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Er Quality Control

scholarly journals Analysis of Quality Control Substrates in Distinct Cellular Compartments Reveals a Unique Role for Rpn4p in Tolerating Misfolded Membrane Proteins

2009 ◽  
Vol 20 (3) ◽  
pp. 1006-1019 ◽  
Author(s):  
Meredith Boyle Metzger ◽  
Susan Michaelis
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Transcriptional Response ◽  
Transcriptional Responses ◽  
Er Quality Control ◽  
Yeast Viability ◽  
Severe Impairment ◽  
Proteasomal Genes ◽  
The Unfolded Protein Response ◽  
Cellular Compartments

ER quality control (ERQC) prevents the exit of misfolded secretory and membrane proteins from the ER. A critical aspect of ERQC is a transcriptional response called the unfolded protein response (UPR), which up-regulates genes that enable cells to cope with misfolded, ER-retained proteins. In this study, we compare the transcriptional responses in yeast resulting from the acute expression of misfolded proteins residing in three different cellular compartments (the ER lumen, membrane, and cytosol), and find that each elicits a distinct transcriptional response. The classical UPR response, here-designated UPR-L, is induced by the ER lumenal misfolded protein, CPY*. The UPR-Cyto response is induced by the cytosolic protein, VHL-L158P, and is characterized by a rapid, transient induction of cytosolic chaperones similar to the heat-shock response. In contrast, the misfolded membrane protein with a cystolic lesion, Ste6p*, elicits a unique response designated UPR-M/C, characterized by the modest induction of >20 genes regulated by Rpn4p, an activator of proteasomal genes. Independently, we identified several genes required for yeast viability during UPR-M/C stress, but not UPR-L or UPR-Cyto stress. Among these is RPN4, highlighting the importance of the Rpn4p-dependent response in tolerating UPR-M/C stress. Further analysis suggests the requirement for Rpn4p reflects severe impairment of the proteasome by UPR-M/C stress.

scholarly journals A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

2020 ◽  
Author(s):  
Madlen Stephani ◽  
Lorenzo Picchianti ◽  
Alexander Gajic ◽  
Rebecca Beveridge ◽  
Emilio Skarwan ◽  
...  
Keyword(s):  
Quality Control ◽  
Er Stress ◽  
Mammalian Cells ◽  
Control Mechanisms ◽  
Receptor Complex ◽  
Er Quality Control ◽  
Proteotoxic Stress ◽  
Binding Epitope ◽  
Quality Control Mechanism ◽  
Passenger Proteins

SummaryEukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER. Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control at the ER.

scholarly journals Quality control in tRNA charging -- editing of homocysteine.

2011 ◽  
Vol 58 (2) ◽  
Author(s):  
Hieronim Jakubowski
Keyword(s):  
Amino Acids ◽  
Quality Control ◽  
Control Point ◽  
Building Blocks ◽  
Trna Synthetase ◽  
Nutritional Deficiencies ◽  
Homocysteine Thiolactone ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Living Organisms

All living organisms conduct protein synthesis with a high degree of accuracy maintained in the transmission and flow of information from a gene to protein product. One crucial 'quality control' point in maintaining a high level of accuracy is the selectivity by which aminoacyl-tRNA synthetases furnish correctly activated amino acids, attached to tRNA species, as the building blocks for growing protein chains. When differences in binding energies of amino acids to an aminoacyl-tRNA synthetase are inadequate, editing is used as a major determinant of enzyme selectivity. Some incorrect amino acids are edited at the active site before the transfer to tRNA (pre-transfer editing), while others are edited after transfer to tRNA at a separate editing site (post-transfer editing). Access of natural non-protein amino acids, such as homocysteine, homoserine, or ornithine to the genetic code is prevented by the editing function of aminoacyl-tRNA synthetases. Disabling editing function leads to tRNA mischarging errors and incorporation of incorrect amino acids into protein, which is detrimental to cell homeostasis and inhibits growth. Continuous homocysteine editing by methionyl-tRNA synthetase, resulting in the synthesis of homocysteine thiolactone, is part of the process of tRNA aminoacylation in living organisms, from bacteria to man. Excessive homocysteine thiolactone synthesis in hyperhomocysteinemia caused by genetic or nutritional deficiencies is linked to human vascular and neurological diseases.

scholarly journals A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Madlen Stephani ◽  
Lorenzo Picchianti ◽  
Alexander Gajic ◽  
Rebecca Beveridge ◽  
Emilio Skarwan ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mammalian Cells ◽  
Control Mechanisms ◽  
Receptor Complex ◽  
Er Quality Control ◽  
Proteotoxic Stress ◽  
Quality Control Mechanism ◽  
Passenger Proteins

Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the endoplasmic reticulum (ER). Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.

scholarly journals Endoplasmic Reticulum Stress and Neurodegeneration in Rats Neonatally Infected with Borna Disease Virus

2006 ◽  
Vol 80 (17) ◽  
pp. 8613-8626 ◽  
Author(s):  
B. L. Williams ◽  
W. I. Lipkin
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Fate ◽  
Disease Virus ◽  
Critical Determinant ◽  
Er Quality Control ◽  
Borna Disease Virus ◽  
Control Signals ◽  
Borna Disease

ABSTRACT Borna disease virus infection of neonatal rats results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus and cerebellum (neonatal Borna disease [NBD]). The cellular mechanisms leading to neurodevelopmental damage in NBD have not been fully elucidated. Insights into this model may have general implications for understanding the pathogenesis of virus-associated neurodevelopmental damage. Here we report the presence of endoplasmic reticulum (ER) stress markers and activation of the unfolded protein response in the NBD hippocampus and cerebellum. Specific findings included enhanced PERK-mediated phosphorylation of eif2α and concomitant regulation of ATF4 translation; IRE1-mediated splicing of XBP1 mRNA; and cleavage of the ATF6 protein in NBD rat brains. We found evidence for regional and cell type-specific divergence in the expression of ER stress-induced proapoptotic and quality control signals. Our results demonstrate that ER stress induction in death-susceptible Purkinje neurons in NBD is associated with the expression of the proapoptotic molecule CHOP in the absence of compensatory expression of the ER quality control molecules Bip and protein disulfide isomerase. In contrast, ER stress in death-resistant astrocytes is associated with complementary expression of CHOP and ER quality control signals. These results implicate an imbalance between ER stress-mediated apoptosis and survival signaling as a critical determinant of neural cell fate in NBD.

scholarly journals Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice

2004 ◽  
Vol 24 (18) ◽  
pp. 8007-8017 ◽  
Author(s):  
Hiromichi Hamada ◽  
Masashi Suzuki ◽  
Shigeki Yuasa ◽  
Naoya Mimura ◽  
Norihiro Shinozuka ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Transgenic Mice ◽  
Er Stress ◽  
Dilated Cardiomyopathy ◽  
Protein Aggregates ◽  
Mutant Mice ◽  
Er Quality Control ◽  
Kdel Receptor

ABSTRACT Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca2+ current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.

scholarly journals Tay–Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum–associated degradation

2016 ◽  
Vol 27 (24) ◽  
pp. 3813-3827 ◽  
Author(s):  
Devin Dersh ◽  
Yuichiro Iwamoto ◽  
Yair Argon
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control Mechanisms ◽  
Permissive Temperature ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Er Quality Control ◽  
Tay Sachs Disease ◽  
Hexosaminidase A ◽  
Α Chain

Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay–Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. The α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type α. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA β chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant α degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant α folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD.

scholarly journals A new murine model of Barth Syndrome neutropenia links TAFAZZIN deficiency to increased ER stress induced apoptosis

2022 ◽  
Author(s):  
Jihee Sohn ◽  
Jelena Milosevic ◽  
Thomas Brouse ◽  
Najihah Aziz ◽  
Jenna Elkhoury ◽  
...  
Keyword(s):  
Er Stress ◽  
Murine Model ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Model System ◽  
Barth Syndrome ◽  
Loss Of Function ◽  
Inner Mitochondrial Membrane ◽  
Hematopoietic Stem ◽  
Increased Sensitivity

Barth syndrome is an inherited X-linked disorder that leads to cardiomyopathy, skeletal myopathy and neutropenia. These symptoms result from the loss of function of the enzyme TAFAZZIN, a transacylase located in the inner mitochondrial membrane that is responsible for the final steps of cardiolipin production. The link between defective cardiolipin maturation and neutropenia remains unclear. To address potential mechanisms of neutropenia, we examined myeloid progenitor development within the fetal liver of TAFAZZIN knock-out animals as well as within the adult bone marrow of wild-type recipients transplanted with TAFAZZIN KO hematopoietic stem cells. We also used the ER Hoxb8 system of conditional immortalization to establish a new murine model system for the ex vivo study of TAFAZZIN-deficient neutrophils. The TAFAZZIN KO cells demonstrated the expected dramatic differences in cardiolipin maturation that result from a lack of TAFAZZIN enzyme activity. Contrary to our hypothesis, we did not identify any significant differences in neutrophil development or neutrophil function across a variety of assays including phagocytosis, and the production of cytokines or reactive oxygen species. However, transcriptomic analysis of the TAFAZZIN-deficient neutrophil progenitors demonstrated an upregulation of markers of endoplasmic reticulum stress and confirmatory testing demonstrated that the TAFAZZIN-deficient cells had increased sensitivity to certain ER stress mediated and non ER stress mediated triggers of apoptosis. While the link between increased sensitivity to apoptosis and the variably penetrant neutropenia phenotype seen in some Barth syndrome patients remains to be clarified, our studies and new model system set a foundation for further investigation.

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