scholarly journals Regulation of the ER stress response by a mitochondrial microprotein

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Qian Chu ◽  
Thomas F. Martinez ◽  
Sammy Weiser Novak ◽  
Cynthia J. Donaldson ◽  
Dan Tan ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Mitochondrial Outer Membrane ◽  
Unfolded Proteins ◽  
Functional Studies ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Organelle Communication ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER–mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

scholarly journals The Role of the ER-Induced UPR Pathway and the Efficacy of Its Inhibitors and Inducers in the Inhibition of Tumor Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Anna Walczak ◽  
Kinga Gradzik ◽  
Jacek Kabzinski ◽  
Karolina Przybylowska-Sygut ◽  
Ireneusz Majsterek
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Proteins ◽  
Cell Protection ◽  
Protection Mechanism ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Cancer is the second most frequent cause of death worldwide. It is considered to be one of the most dangerous diseases, and there is still no effective treatment for many types of cancer. Since cancerous cells have a high proliferation rate, it is pivotal for their proper functioning to have the well-functioning protein machinery. Correct protein processing and folding are crucial to maintain tumor homeostasis. Endoplasmic reticulum (ER) stress is one of the leading factors that cause disturbances in these processes. It is induced by impaired function of the ER and accumulation of unfolded proteins. Induction of ER stress affects many molecular pathways that cause the unfolded protein response (UPR). This is the way in which cells can adapt to the new conditions, but when ER stress cannot be resolved, the UPR induces cell death. The molecular mechanisms of this double-edged sword process are involved in the transition of the UPR either in a cell protection mechanism or in apoptosis. However, this process remains poorly understood but seems to be crucial in the treatment of many diseases that are related to ER stress. Hence, understanding the ER stress response, especially in the aspect of pathological consequences of UPR, has the potential to allow us to develop novel therapies and new diagnostic and prognostic markers for cancer.

scholarly journals The unfolded protein response in relation to mitochondrial biogenesis in skeletal muscle cells

2017 ◽  
Vol 312 (5) ◽  
pp. C583-C594 ◽  
Author(s):  
Zahra S. Mesbah Moosavi ◽  
David A. Hood
Keyword(s):  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Muscle Cells ◽  
Unfolded Proteins ◽  
Protein Levels ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Mitochondrial Adaptations

Mitochondria comprise both nuclear and mitochondrially encoded proteins requiring precise stoichiometry for their integration into functional complexes. The augmented protein synthesis associated with mitochondrial biogenesis results in the accumulation of unfolded proteins, thus triggering cellular stress. As such, the unfolded protein responses emanating from the endoplasmic reticulum (UPRER) or the mitochondrion (UPRMT) are triggered to ensure correct protein handling. Whether this response is necessary for mitochondrial adaptations is unknown. Two models of mitochondrial biogenesis were used: muscle differentiation and chronic contractile activity (CCA) in murine muscle cells. After 4 days of differentiation, our findings depict selective activation of the UPRMTin which chaperones decreased; however, Sirt3 and UPRERmarkers were elevated. To delineate the role of ER stress in mitochondrial adaptations, the ER stress inhibitor TUDCA was administered. Surprisingly, mitochondrial markers COX-I, COX-IV, and PGC-1α protein levels were augmented up to 1.5-fold above that of vehicle-treated cells. Similar results were obtained in myotubes undergoing CCA, in which biogenesis was enhanced by ~2–3-fold, along with elevated UPRMTmarkers Sirt3 and CPN10. To verify whether the findings were attributable to the terminal UPRERbranch directed by the transcription factor CHOP, cells were transfected with CHOP siRNA. Basally, COX-I levels increased (~20%) and COX-IV decreased (~30%), suggesting that CHOP influences mitochondrial composition. This effect was fully restored by CCA. Therefore, our results suggest that mitochondrial biogenesis is independent of the terminal UPRER. Under basal conditions, CHOP is required for the maintenance of mitochondrial composition, but not for differentiation- or CCA-induced mitochondrial biogenesis.

scholarly journals Protein Serine/Threonine Phosphatase Ptc2p Negatively Regulates the Unfolded-Protein Response by Dephosphorylating Ire1p Kinase

1998 ◽  
Vol 18 (4) ◽  
pp. 1967-1977 ◽  
Author(s):  
Ajith A. Welihinda ◽  
Witoon Tirasophon ◽  
Sarah R. Green ◽  
Randal J. Kaufman
Keyword(s):  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Null Alleles ◽  
Dependent Manner ◽  
Unfolded Proteins ◽  
Interaction Domain ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

ABSTRACT Cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by increasing the transcription of the genes encoding ER-resident chaperone proteins. Ire1p is a transmembrane protein kinase that transmits the signal from unfolded proteins in the lumen of the ER by a mechanism that requires oligomerization andtrans-autophosphorylation of its cytoplasmic-nucleoplasmic kinase domain. Activation of Ire1p induces a novel spliced form ofHAC1 mRNA that produces Hac1p, a transcription factor that is required for activation of the transcription of genes under the control of the unfolded-protein response (UPR) element. Searching for proteins that interact with Ire1p in Saccharomyces cerevisiae, we isolated PTC2, which encodes a serine/threonine phosphatase of type 2C. The Ptc2p interaction with Ire1p is specific, direct, dependent on Ire1p phosphorylation, and mediated through a kinase interaction domain within Ptc2p. Ptc2p dephosphorylates Ire1p efficiently in an Mg2+-dependent manner in vitro. PTC2 is nonessential for growth and negatively regulates the UPR pathway. Strains carrying null alleles ofPTC2 have a three- to fourfold-increased UPR and increased levels of spliced HAC1 mRNA. Overexpression of wild-type Ptc2p but not catalytically inactive Ptc2p reduces levels of splicedHAC1 mRNA and attenuates the UPR, demonstrating that the phosphatase activity of Ptc2p is required for regulation of the UPR. These results demonstrate that Ptc2p downregulates the UPR by dephosphorylating Ire1p and reveal a novel mechanism of regulation in the UPR pathway upstream of the HAC1 mRNA splicing event.

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

scholarly journals Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 19 (21) ◽  
pp. 1902-1917 ◽  
Author(s):  
Guangyu Zhang ◽  
Xiaoding Wang ◽  
Thomas G. Gillette ◽  
Yingfeng Deng ◽  
Zhao V. Wang
Keyword(s):  
Cardiovascular Disease ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Protein Translation ◽  
Ample Evidence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Chronic Disturbance ◽  
The Unfolded Protein Response ◽  
Protein Response

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

scholarly journals Stress macht Zellen resistent gegen Folsäure-basierte Chemotherapeutika

BIOspektrum ◽  
2020 ◽  
Vol 26 (6) ◽  
pp. 609-611
Author(s):  
Robert Ahrends ◽  
Jan Medenbach
Keyword(s):  
Gene Regulation ◽  
Stress Response ◽  
Molecular Mechanisms ◽  
Cellular Stress Response ◽  
Resistance To Therapy ◽  
Unfolded Protein ◽  
Stress Response Pathway ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The unfolded protein response (UPR), a cellular stress response pathway, is broadly implicated in disease and resistance to therapy. The molecular mechanisms that drive stress-mediated chemoresistance are, however, only poorly understood. We have employed a multiomics approach to determine UPR-induced gene regulation, revealing the UPR regulon. We further observe metabolic rewiring upon stress and resistance to Methotrexate, a widely-employed therapeutic reagent. The precise molecular characterization of the pathway driving resistance might lead to novel concepts in cancer therapy.

scholarly journals MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response

2012 ◽  
Vol 196 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Andrew E. Byrd ◽  
Ileana V. Aragon ◽  
Joseph W. Brewer
Keyword(s):  
Unfolded Protein Response ◽  
Cell Fate ◽  
Translational Control ◽  
Secretory Pathway ◽  
Signaling System ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Secretory Capacity

Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a multifaceted signaling system coordinating translational control and gene transcription to promote cellular adaptation and survival. Microribonucleic acids (RNAs; miRNAs), single-stranded RNAs that typically function as posttranscriptional modulators of gene activity, have been shown to inhibit translation of certain secretory pathway proteins during the UPR. However, it remains unclear whether miRNAs regulate UPR signaling effectors directly. In this paper, we report that a star strand miRNA, miR-30c-2* (recently designated miR-30c-2-3p), is induced by the protein kinase RNA activated–like ER kinase (PERK) pathway of the UPR and governs expression of XBP1 (X-box binding protein 1), a key transcription factor that augments secretory capacity and promotes cell survival in the adaptive UPR. These data provide the first link between an miRNA and direct regulation of the ER stress response and reveal a novel molecular mechanism by which the PERK pathway, via miR-30c-2*, influences the scale of XBP1-mediated gene expression and cell fate in the UPR.

scholarly journals Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Elena Ferri ◽  
Adrien Le Thomas ◽  
Heidi Ackerly Wallweber ◽  
Eric S. Day ◽  
Benjamin T. Walters ◽  
...  
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Endoplasmic Reticulum Membrane ◽  
Cellular Activity ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Dimeric Unit ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Lumenal Domain

AbstractInositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.

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