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 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 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 ◽  
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 Complementary Signaling Pathways Regulate the Unfolded Protein Response and Are Required for C. elegans Development

Cell ◽  
2001 ◽  
Vol 107 (7) ◽  
pp. 893-903 ◽  
Author(s):  
Xiaohua Shen ◽  
Ronald E. Ellis ◽  
Kyungho Lee ◽  
Chuan-Yin Liu ◽  
Kun Yang ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Signaling Pathways ◽  
C Elegans ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Cysteine cross-linking in native membranes establishes the transmembrane architecture of Ire1

2021 ◽  
Vol 220 (8) ◽  
Author(s):  
Kristina Väth ◽  
Carsten Mattes ◽  
John Reinhard ◽  
Roberto Covino ◽  
Heike Stumpf ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Cross Linking ◽  
Secretory Proteins ◽  
Transmembrane Helices ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Protein Load

The ER is a key organelle of membrane biogenesis and crucial for the folding of both membrane and secretory proteins. Sensors of the unfolded protein response (UPR) monitor the unfolded protein load in the ER and convey effector functions for maintaining ER homeostasis. Aberrant compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent activators of the UPR. How the distinct signals from lipid bilayer stress and unfolded proteins are processed by the conserved UPR transducer Ire1 remains unknown. Here, we have generated a functional, cysteine-less variant of Ire1 and performed systematic cysteine cross-linking experiments in native membranes to establish its transmembrane architecture in signaling-active clusters. We show that the transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped configuration independent of the primary cause for ER stress. This suggests that different forms of stress converge in a common, signaling-active transmembrane architecture of Ire1.

scholarly journals Live imaging of the co-translational recruitment of XBP1 mRNA to the ER and its processing by diffuse, non-polarized IRE1a.

2021 ◽  
Author(s):  
Silvia Gomez-Puerta ◽  
Roberto Ferrero ◽  
Tobias Hochstoeger ◽  
Ivan Zubiri ◽  
Jeffrey A. Chao ◽  
...  
Keyword(s):  
Er Stress ◽  
Single Molecule ◽  
Oligomeric State ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Imaging Approach ◽  
The Unfolded Protein Response ◽  
Large Clusters ◽  
Protein Response ◽  
Er Membrane

Endoplasmic reticulum (ER) to nucleus homeostatic signalling, known as the unfolded protein response (UPR), relies on the non-canonical splicing of XBP1 mRNA. The molecular switch that initiates splicing is the oligomerization of the ER stress sensor and UPR endonuclease IRE1a. While IRE1a can form large clusters that have been proposed to function as XBP1 processing centers on the ER, the actual oligomeric state of active IRE1a complexes as well as the targeting mechanism that recruits XBP1 to IRE1a oligomers, remain unknown. Here, we used a single molecule imaging approach to directly monitor the recruitment of individual XBP1 transcripts to the ER surface. We confirmed that stable ER association of unspliced XBP1 mRNA is established through HR2-dependent targeting and relies on active translation. In addition, we show that IRE1a-catalyzed splicing mobilizes XBP1 mRNA from the ER membrane in response to ER stress. Surprisingly, we find that XBP1 transcripts are not recruited into large IRE1a clusters, which only assemble upon overexpression of fluorescently-tagged IRE1a during ER stress. Our findings support a model where ribosome-engaged, ER-poised XBP1 mRNA is processed by functional IRE1a assemblies that are homogenously distributed throughout the ER membrane.

scholarly journals Auxin confers protection against ER stress in Caenorhabditis elegans

2020 ◽  
Author(s):  
A. Bhoi ◽  
F. Palladino ◽  
P. Fabrizio
Keyword(s):  
Er Stress ◽  
Developmental Stages ◽  
Cultured Cells ◽  
Central Function ◽  
Extreme Caution ◽  
C Elegans ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Open Question

AbstractAuxins are plant growth regulators that influence most aspects of plant development through complex mechanisms. The development of an auxin-inducible degradation (AID) system has enabled rapid, conditional protein depletion in yeast and cultured cells. More recently, the system was successfully adapted to C. elegans to achieve auxin-dependent degradation of targets in all tissues and developmental stages. Whether auxin treatment alone has an impact on nematode physiology is an open question. Here we show that indole-3-acetic acid (IAA), the auxin most commonly used to trigger AID in worms, functions through the conserved IRE-1/XBP-1 branch of the Unfolded Protein Response (UPR) to promote resistance to Endoplasmic Reticulum (ER) stress. Because of the central function played by the UPR in protein folding, lipid biosynthesis and lifespan regulation, these results suggest that extreme caution should be exercised when using the AID system to study these and related processes.

scholarly journals The Unfolded Protein Response as a Guardian of the Secretory Pathway

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2965
Author(s):  
Toni Radanović ◽  
Robert Ernst
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Storage Lipids ◽  
Unfolded Protein ◽  
Membrane Stiffness ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Membrane

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

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