scholarly journals Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

2020 ◽  
Vol 219 (7) ◽  
Author(s):  
Nurulain Ho ◽  
Wei Sheng Yap ◽  
Jiaming Xu ◽  
Haoxi Wu ◽  
Jhee Hong Koh ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Stress Responses ◽  
Metabolic Diseases ◽  
Membrane Integrity ◽  
Membrane Lipid ◽  
Compensatory Response ◽  
C Elegans ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Er Membrane

Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

scholarly journals ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

2019 ◽  
Author(s):  
Nurulain Ho ◽  
Haoxi Wu ◽  
Jiaming Xu ◽  
Jhee Hong Koh ◽  
Wei Sheng Yap ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Metabolic Diseases ◽  
Membrane Integrity ◽  
Membrane Lipid ◽  
C Elegans ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Yeast Mutants ◽  
Er Membrane

SUMMARYMembrane integrity at the endoplasmic reticulum (ER) is tightly regulated and is implicated in metabolic diseases when compromised. Using an engineered sensor that exclusively activates the unfolded protein response (UPR) during aberrant ER membrane lipid composition, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and are conserved in C. elegans. To systematically validate yeast mutants disrupting ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensing switch in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory pathway in which LBS and proteotoxic stress-induced UPR deploy divergent transcriptional programs. Together, these findings reveal the UPR program as the sum of two independent stress events and could be exploited for future therapeutic intervention.

scholarly journals Combining auxin-induced degradation and RNAi screening identifies novel genes involved in lipid bilayer stress sensing in Caenorhabditis elegans

2020 ◽  
Author(s):  
Richard Venz ◽  
Anastasiia Korosteleva ◽  
Collin Y. Ewald
Keyword(s):  
Transcription Factors ◽  
Stress Response ◽  
Lipid Bilayer ◽  
Screening Strategy ◽  
Suppressor Genes ◽  
C Elegans ◽  
Unfolded Protein ◽  
Stress Sensing ◽  
The Unfolded Protein Response ◽  
Almost All

AbstractAlteration of the lipid composition of biological membranes interferes with their function and can cause tissue damage by triggering apoptosis. Upon lipid bilayer stress, the endoplasmic reticulum mounts a stress response that is similar to the unfolded protein response. However, only a few genes are known to regulate lipid bilayer stress. Here, we performed a suppressor screen that combined the auxin-inducible degradation (AID) system with conventional RNAi in C. elegans to identify members of the lipid bilayer stress response. AID-mediated knockdown of the mediator MDT-15, a protein required for the upregulation of fatty acid desaturases, caused activation of a lipid bilayer stress sensitive reporters. We screened through almost all C. elegans kinases and transcription factors using RNAi by feeding. We report the identification of 8 genes that have not been implicated previously with lipid bilayer stress before in C. elegans. These suppressor genes include skn-1/NRF1,2,3 and let-607/CREB3. Our candidate suppressor genes suggest a network of transcription factors and the integration of multiple tissues for a centralized lipotoxicity response in the intestine. Additionally, we propose and demonstrate the proof-of-concept for combining AID and RNAi as a new screening strategy.

scholarly journals Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans

Science ◽  
2020 ◽  
Vol 367 (6476) ◽  
pp. 436-440 ◽  
Author(s):  
Ashley E. Frakes ◽  
Melissa G. Metcalf ◽  
Sarah U. Tronnes ◽  
Raz Bar-Ziv ◽  
Jenni Durieux ◽  
...  
Keyword(s):  
Er Stress ◽  
Life Span ◽  
Glial Cells ◽  
Stress Responses ◽  
Stress Resistance ◽  
Life Span Extension ◽  
C Elegans ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The ability of the nervous system to sense cellular stress and coordinate protein homeostasis is essential for organismal health. Unfortunately, stress responses that mitigate disturbances in proteostasis, such as the unfolded protein response of the endoplasmic reticulum (UPRER), become defunct with age. In this work, we expressed the constitutively active UPRER transcription factor, XBP-1s, in a subset of astrocyte-like glia, which extended the life span in Caenorhabditis elegans. Glial XBP-1s initiated a robust cell nonautonomous activation of the UPRER in distal cells and rendered animals more resistant to protein aggregation and chronic ER stress. Mutants deficient in neuropeptide processing and secretion suppressed glial cell nonautonomous induction of the UPRER and life-span extension. Thus, astrocyte-like glial cells play a role in regulating organismal ER stress resistance and longevity.

scholarly journals HSP-4/BiP expression in secretory cells is regulated by a lineage-dependent differentiation program and not by the unfolded protein response

2018 ◽  
Author(s):  
Ji Zha ◽  
Jasmine Alexander-Floyd ◽  
Tali Gidalevitz
Keyword(s):  
Unfolded Protein Response ◽  
Secretory Cells ◽  
C Elegans ◽  
Unfolded Protein ◽  
Daughter Cells ◽  
Developmental Program ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response ◽  
Anticipatory Activation

AbstractDifferentiation of secretory cells leads to sharp increases in protein synthesis, challenging ER proteostasis. Anticipatory activation of the unfolded protein response (UPR) prepares cells for the onset of secretory function by expanding the ER size and folding capacity. How cells ensure that the repertoire of induced chaperones matches their post-differentiation folding needs is not well understood. We find that during differentiation of stem-like seam cells, a typical UPR target, the C. elegans BiP homologue HSP-4, is selectively induced in alae-secreting daughter cells, but is repressed in hypodermal daughter cells. Surprisingly, this lineage-dependent induction bypasses the requirement for UPR signaling, and instead is controlled by a specific developmental program. The repression of HSP-4 in hypodermal-fated cells requires a transcriptional regulator BLMP-1/BLIMP1, involved in differentiation of mammalian secretory cells. The HSP-4 induction is anticipatory, and is required for the integrity of secreted alae. Thus, differentiation programs can directly control a broad-specificity chaperone that is normally stress-dependent, to ensure the integrity of secreted proteins.

scholarly journals Combining Auxin-Induced Degradation and RNAi Screening Identifies Novel Genes Involved in Lipid Bilayer Stress Sensing in Caenorhabditis elegans

2020 ◽  
Vol 10 (11) ◽  
pp. 3921-3928 ◽  
Author(s):  
Richard Venz ◽  
Anastasiia Korosteleva ◽  
Elisabeth Jongsma ◽  
Collin Y. Ewald
Keyword(s):  
Transcription Factors ◽  
Stress Response ◽  
Lipid Bilayer ◽  
Screening Strategy ◽  
Suppressor Genes ◽  
C Elegans ◽  
Link Type ◽  
Conserved Genes ◽  
Stress Sensing ◽  
The Unfolded Protein Response

Alteration of the lipid composition of biological membranes interferes with their function and can cause tissue damage by triggering apoptosis. Upon lipid bilayer stress, the endoplasmic reticulum mounts a stress response similar to the unfolded protein response. However, only a few genes are known to regulate lipid bilayer stress. We performed a suppressor screen that combined the auxin-inducible degradation (AID) system with conventional RNAi in C. elegans to identify members of the lipid bilayer stress response. AID-mediated degradation of the mediator MDT-15, a protein required for the upregulation of fatty acid desaturases, induced the activation of lipid bilayer stress-sensitive reporters. We screened through most C. elegans kinases and transcription factors by feeding RNAi. We discovered nine genes that suppressed the lipid bilayer stress response in C. elegans. These suppressor genes included drl-1/MAP3K3, gsk-3/GSK3, let-607/CREB3, ire-1/IRE1, and skn-1/NRF1,2,3. Our candidate suppressor genes suggest a network of transcription factors and the integration of multiple tissues for a centralized lipotoxicity response in the intestine. Thus, we demonstrated proof-of-concept for combining AID and RNAi as a new screening strategy and identified eight conserved genes that had not previously been implicated in the lipid bilayer stress response.

scholarly journals Herpesviruses and the Unfolded Protein Response

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 17 ◽  
Author(s):  
Benjamin P. Johnston ◽  
Craig McCormick
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Immune Surveillance ◽  
Lytic Replication ◽  
Glycoprotein Synthesis ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Molecular Events ◽  
The Unfolded Protein Response ◽  
Protein Response

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

Chemotherapy: induction of stress responses

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S115-S124 ◽  
Author(s):  
E Tiligada
Keyword(s):  
Anticancer Agents ◽  
Stress Responses ◽  
Chemotherapeutic Agents ◽  
Clinical Value ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Shock Proteins ◽  
And Function ◽  
Protein Response ◽  
Functional Components

Eukaryotic cells, from yeast to mammals, respond and adapt to environmental and microenvironmental stressors by evolutionary conserved multicomponent endogenous systems that utilise a network of signal transduction pathways to regulate the adaptive and protective phenotype. The balance between cell survival and cell death is decisive for sensitivity or resistance to DNA-damaging chemotherapeutic agents. Anticancer drugs may themselves act as stressors to induce adaptive signals that could limit their clinical value. Related research has been focused on the modulation of the expression and function of the heat shock proteins, the unfolded protein response, the mechanisms of subcellular translocation of signalling components, the genomic and non-genomic actions of drugs and endogenous functional components like hormonal pathways, the input of inflammation and alterations in the microenvironmental milieu and on the control of the cell cycle and proliferation. The outcome seems to be driven by the first-line responses that support cellular integrity and by specific mechanisms that depend on the type of cell and the nature, and duration and severity of the noxious stimulus. Data obtained from experimental organisms like the yeast have added valuable information on the basic conservation in cellular stress-related processes in eukaryotes and on the consequences that may accompany the adaptive and protective phenotype during the stress response to anticancer agents. Understanding the complex molecular pathways mediating these processes has started to contribute to the reevaluation of the current therapeutic regiments and to revolutionise the approaches for improved anticancer therapy.

scholarly journals Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans

2021 ◽  
Vol 7 (26) ◽  
pp. eabg3012
Author(s):  
Giuseppe Calculli ◽  
Hyun Ju Lee ◽  
Koning Shen ◽  
Uyen Pham ◽  
Marija Herholz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Aggregation ◽  
Germ Line ◽  
Wnt Signaling Pathway ◽  
Germline Stem Cells ◽  
C Elegans ◽  
Unfolded Protein ◽  
Somatic Tissues ◽  
Intracellular Changes ◽  
The Unfolded Protein Response

Protein aggregation causes intracellular changes in neurons, which elicit signals to modulate proteostasis in the periphery. Beyond the nervous system, a fundamental question is whether other organs also communicate their proteostasis status to distal tissues. Here, we examine whether proteostasis of the germ line influences somatic tissues. To this end, we induce aggregation of germline-specific PGL-1 protein in germline stem cells of Caenorhabditis elegans. Besides altering the intracellular mitochondrial network of germline cells, PGL-1 aggregation also reduces the mitochondrial content of somatic tissues through long-range Wnt signaling pathway. This process induces the unfolded protein response of the mitochondria in the soma, promoting somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington’s and amyotrophic lateral sclerosis. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.

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