The SWI/SNF and RSC Cooperatively Remodel the Promoters of Unfolded Protein Response Targets and Heat Shock Genes

The ATP-dependent chromatin remodelling complexes maintain the chromatin dynamics, enabling the gene expression or its silencing. The SWI/SNF subfamily remodelers (SWI/SNF and RSC) generally promote gene expression by displacing or evicting nucleosomes at the promoter regions. Their action creates a nucleosome-depleted region where transcription machinery accesses the DNA. Their involvement has been shown critical for the induction of stress-responsive transcription programs. Although the role of SWI/SNF and RSC complexes in transcription regulation of heat shock responsive genes is well studied, their involvement at other pathway genes such as UPR, HSP and PQC is less known. In this study, we showed that the SWI/SNF occupies promoters of UPR, HSP and PQC genes in response to the unfolded protein stress, and its recruitment at UPR promoters is dependent on the Hac1 transcription factor and other epigenetic factors like Ada2 and Ume6. Disruption of SWI/SNF’s activity does not affect the remodelling of these promoters or gene expression. However, inactivation of both RSC and SWI/SNF complexes diminishes expression of most of the UPR, HSP and PQC genes tested. Altogether these results suggest that these two remodelers work together or one compensates the loss of the other to ensure optimal induction of the stress-responsive genes.

Degradation of a Short-lived Glycoprotein from the Lumen of the Endoplasmic Reticulum: The Role of N-linked Glycans and the Unfolded Protein Response

Molecular Biology of the Cell ◽

10.1091/mbc.10.12.4059 ◽

1999 ◽

Vol 10 (12) ◽

pp. 4059-4073 ◽

Cited By ~ 58

Author(s):

Maddalena de Virgilio ◽

Claudia Kitzmüller ◽

Eva Schwaiger ◽

Michael Klein ◽

Gert Kreibich ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

The Other ◽

Slow Phase ◽

Type I ◽

Unfolded Protein ◽

Other Hand ◽

We are studying endoplasmic reticulum–associated degradation (ERAD) with the use of a truncated variant of the type I ER transmembrane glycoprotein ribophorin I (RI). The mutant protein, RI332, containing only the N-terminal 332 amino acids of the luminal domain of RI, has been shown to interact with calnexin and to be a substrate for the ubiquitin-proteasome pathway. When RI332 was expressed in HeLa cells, it was degraded with biphasic kinetics; an initial, slow phase of ∼45 min was followed by a second phase of threefold accelerated degradation. On the other hand, the kinetics of degradation of a form of RI332 in which the single used N-glycosylation consensus site had been removed (RI332-Thr) was monophasic and rapid, implying a role of the N-linked glycan in the first proteolytic phase. RI332degradation was enhanced when the binding of glycoproteins to calnexin was prevented. Moreover, the truncated glycoprotein interacted with calnexin preferentially during the first proteolytic phase, which strongly suggests that binding of RI332 to the lectin-like protein may result in the slow, initial phase of degradation. Additionally, mannose trimming appears to be required for efficient proteolysis of RI332. After treatment of cells with the inhibitor of N-glycosylation, tunicamycin, destruction of the truncated RI variants was severely inhibited; likewise, in cells preincubated with the calcium ionophore A23187, both RI332 and RI332-Thr were stabilized, despite the presence or absence of the N-linked glycan. On the other hand, both drugs are known to trigger the unfolded protein response (UPR), resulting in the induction of BiP and other ER-resident proteins. Indeed, only in drug-treated cells could an interaction between BiP and RI332 and RI332-Thr be detected. Induction of BiP was also evident after overexpression of murine Ire1, an ER transmembrane kinase known to play a central role in the UPR pathway; at the same time, stabilization of RI332 was observed. Together, these results suggest that binding of the substrate proteins to UPR-induced chaperones affects their half lives.

Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

International Journal of Molecular Sciences ◽

10.3390/ijms22052567 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2567

Author(s):

Yann S. Gallot ◽

Kyle R. Bohnert

Keyword(s):

Skeletal Muscle ◽

Er Stress ◽

Smooth Endoplasmic Reticulum ◽

Skeletal Muscle Atrophy ◽

Unfolded Protein ◽

The Individual ◽

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

Histone Modifying Enzymes in Gynaecological Cancers

Cancers ◽

10.3390/cancers13040816 ◽

2021 ◽

Vol 13 (4) ◽

pp. 816

Author(s):

Priya Ramarao-Milne ◽

Olga Kondrashova ◽

Sinead Barry ◽

John D. Hooper ◽

Jason S. Lee ◽

...

Keyword(s):

Genome Instability ◽

Cpg Islands ◽

Gene Promoter ◽

Driver Mutations ◽

Promoter Regions ◽

Post Translational Modifications ◽

Chromatin Dynamics ◽

Cancer Types ◽

Histone Modifying Enzymes

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.

An alternatively spliced heat shock transcription factor,OsHSFA2dI, functions in the heat stress-induced unfolded protein response in rice

Plant Biology ◽

10.1111/plb.12267 ◽

2015 ◽

Vol 17 (2) ◽

pp. 419-429 ◽

Cited By ~ 23

Author(s):

Q. Cheng ◽

Y. Zhou ◽

Z. Liu ◽

L. Zhang ◽

G. Song ◽

...

Keyword(s):

Transcription Factor ◽

Heat Stress ◽

Heat Shock ◽

Heat Shock Transcription Factor ◽

Unfolded Protein ◽

Alternatively Spliced ◽

The heat shock response: A case study of chromatin dynamics in gene regulation

Biochemistry and Cell Biology ◽

10.1139/bcb-2012-0075 ◽

2013 ◽

Vol 91 (1) ◽

pp. 42-48 ◽

Cited By ~ 11

Author(s):

Sheila S. Teves ◽

Steven Henikoff

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Heat Shock ◽

Heat Shock Response ◽

Control Of Gene Expression ◽

Pol Ii ◽

Chromatin Dynamics ◽

Regulatory Processes ◽

Shock Response ◽

Rate Limiting

Recent studies in transcriptional regulation using the Drosophila heat shock response system have elucidated many of the dynamic regulatory processes that govern transcriptional activation and repression. The classic view that the control of gene expression occurs at the point of RNA polymerase II (Pol II) recruitment is now giving way to a more complex outlook of gene regulation. Promoter chromatin dynamics coordinate with transcription factor binding to maintain the promoters of active genes accessible. For a large number of genes, the rate-limiting step in Pol II progression occurs during its initial elongation, where Pol II transcribes 30–50 bp and pauses for further signals. These paused genes have unique genic chromatin architecture and dynamics compared with genes where Pol II recruitment is rate limiting for expression. Further elongation of Pol II along the gene causes nucleosome turnover, a continuous process of eviction and replacement, which suggests a potential mechanism for Pol II transit along a nucleosomal template. In this review, we highlight recent insights into transcription regulation of the heat shock response and discuss how the dynamic regulatory processes involved at each transcriptional stage help to generate faithful yet highly responsive gene expression.

Are cachexia-associated tumors transmitTERS of ER stress?

Biochemical Society Transactions ◽

10.1042/bst20210496 ◽

2021 ◽

Author(s):

Ana Sayuri Yamagata ◽

Paula Paccielli Freire

Keyword(s):

Er Stress ◽

Tumor Cells ◽

Cancer Cachexia ◽

Genotoxic Stress ◽

Unfolded Protein ◽

Response To Chemotherapy ◽

Protein Response ◽

Associated Tumors

Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.

A Role for the DnaJ Homologue Scj1p in Protein Folding in the Yeast Endoplasmic Reticulum

The Journal of Cell Biology ◽

10.1083/jcb.143.4.921 ◽

1998 ◽

Vol 143 (4) ◽

pp. 921-933 ◽

Cited By ~ 67

Author(s):

Susana Silberstein ◽

Gabriel Schlenstedt ◽

Pam A. Silver ◽

Reid Gilmore

Keyword(s):

Endoplasmic Reticulum ◽

Physiological Role ◽

Carboxypeptidase Y ◽

Reporter Protein ◽

Unfolded Protein ◽

A Cell ◽

Members of the eukaryotic heat shock protein 70 family (Hsp70s) are regulated by protein cofactors that contain domains homologous to bacterial DnaJ. Of the three DnaJ homologues in the yeast rough endoplasmic reticulum (RER; Scj1p, Sec63p, and Jem1p), Scj1p is most closely related to DnaJ, hence it is a probable cofactor for Kar2p, the major Hsp70 in the yeast RER. However, the physiological role of Scj1p has remained obscure due to the lack of an obvious defect in Kar2p-mediated pathways in scj1 null mutants. Here, we show that the Δscj1 mutant is hypersensitive to tunicamycin or mutations that reduce N-linked glycosylation of proteins. Although maturation of glycosylated carboxypeptidase Y occurs with wild-type kinetics in Δscj1 cells, the transport rate for an unglycosylated mutant carboxypeptidase Y (CPY) is markedly reduced. Loss of Scj1p induces the unfolded protein response pathway, and results in a cell wall defect when combined with an oligosaccharyltransferase mutation. The combined loss of both Scj1p and Jem1p exaggerates the sensitivity to hypoglycosylation stress, leads to further induction of the unfolded protein response pathway, and drastically delays maturation of an unglycosylated reporter protein in the RER. We propose that the major role for Scj1p is to cooperate with Kar2p to mediate maturation of proteins in the RER lumen.

Pancreatic adaptive responses in alcohol abuse: Role of the unfolded protein response

Pancreatology ◽

10.1016/j.pan.2015.01.011 ◽

2015 ◽

Vol 15 (4) ◽

pp. S1-S5 ◽

Cited By ~ 24

Author(s):

Aurelia Lugea ◽

Richard T. Waldron ◽

Stephen J. Pandol

Keyword(s):

Alcohol Abuse ◽

Adaptive Responses ◽

Unfolded Protein ◽

Homocysteine as a Risk Factor for Atherosclerosis: Is Its Conversion toS-Adenosyl-L-Homocysteine the Key to Deregulated Lipid Metabolism?

Journal of Lipids ◽

10.1155/2011/702853 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 21

Author(s):

Oksana Tehlivets

Keyword(s):

Risk Factor ◽

Lipid Metabolism ◽

Mammalian Cells ◽

Yeast Cells ◽

Sterol Synthesis ◽

Unfolded Protein ◽

Strong Product ◽

Homocysteine (Hcy) has been recognized for the past five decades as a risk factor for atherosclerosis. However, the role of Hcy in the pathological changes associated with atherosclerosis as well as the pathological mechanisms triggered by Hcy accumulation is poorly understood. Due to the reversal of the physiological direction of the reaction catalyzed byS-adenosyl-L-homocysteine hydrolase Hcy accumulation leads to the synthesis ofS-adenosyl-L-homocysteine (AdoHcy). AdoHcy is a strong product inhibitor ofS-adenosyl-L-methionine (AdoMet)-dependent methyltransferases, and to date more than 50 AdoMet-dependent methyltransferases that methylate a broad spectrum of cellular compounds including nucleic acids, proteins and lipids have been identified. Phospholipid methylation is the major consumer of AdoMet, both in mammals and in yeast. AdoHcy accumulation induced either by Hcy supplementation or due toS-adenosyl-L-homocysteine hydrolase deficiency results in inhibition of phospholipid methylation in yeast. Moreover, yeast cells accumulating AdoHcy also massively accumulate triacylglycerols (TAG). Similarly, Hcy supplementation was shown to lead to increased TAG and sterol synthesis as well as to the induction of the unfolded protein response (UPR) in mammalian cells. In this review a model of deregulation of lipid metabolism in response to accumulation of AdoHcy in Hcy-associated pathology is proposed.