GO:1903573 negative regulation of response to endoplasmic reticulum stress: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903573 describes any process that stops, prevents or reduces the frequency, rate or extent of a response to endoplasmic reticulum (ER) stress.
• The term is a biological_process branch of the Gene Ontology and is the inverse of positive regulation of ER stress responses; it is not a single gene or protein.
• Key molecular players include the ER-associated degradation (ERAD) machinery SEL1L-HRD1, the ER stress sensor IRE1α, and the transcription factor ATF6.
• Negative regulation of ER stress responses is critical in cancer, metabolic disease, ischemia-reperfusion injury, diabetic kidney disease and neonatal sepsis.
• Dysregulation of this process can promote tumor survival, tissue injury or immune dysfunction, making it a therapeutic target.
• CRISPR knockout, point mutation, knock-in and overexpression models are essential to dissect causal roles of individual regulators in this pathway.
Description
The endoplasmic reticulum (ER) is the primary site for protein folding, lipid synthesis and calcium storage. When the folding capacity of the ER is overwhelmed, cells activate a response to ER stress, often called the unfolded protein response (UPR), to restore homeostasis. The Gene Ontology term GO:1903573, negative regulation of response to endoplasmic reticulum stress, captures any process that stops, prevents or reduces the frequency, rate or extent of that ER stress response. This term is essential for annotating gene products that dampen UPR signaling, either by promoting ER-associated degradation (ERAD), enhancing protein folding, or limiting the duration of stress signaling. Researchers study GO:1903573 because failure to properly restrain ER stress responses contributes to cancer progression, metabolic disorders, ischemia-reperfusion injury and immune dysregulation. For example, IRE1α silences double-stranded RNA to prevent taxane-induced pyroptosis in triple-negative breast cancer, illustrating how negative regulation of ER stress can determine therapeutic outcome. Similarly, GRINA alleviates hepatic ischemia-reperfusion injury by enhancing HRD1-mediated ATF6 ubiquitination, a mechanism that reduces ER stress signaling. These findings highlight that negative regulation of ER stress is not a passive process but an actively controlled network of protein interactions and degradation events. Understanding GO:1903573 requires integrating molecular mechanisms, key regulatory genes and disease contexts. This article provides a research-grade overview based on QuickGO annotation and verified PubMed literature, covering the biological process, key genes, disease links, and CRISPR-based methods to study negative regulation of ER stress responses.
negative regulation of response to endoplasmic reticulum stress At A Glance
| GO ID | GO:1903573 |
|---|---|
| GO term | negative regulation of response to endoplasmic reticulum stress |
| Ontology | biological_process |
| Synonym | down regulation of ER stress response; inhibition of response to ER stress; negative regulation of ER stress response |
| Major function | Suppression or termination of cellular responses to ER stress, including UPR signaling and ERAD |
| Related processes | ER-associated degradation (ERAD), unfolded protein response (UPR), autophagy, ER-phagy |
| Key regulators | SEL1L-HRD1, IRE1α, ATF6, GRINA, GSTK1, RETREG1/FAM134B |
| Disease relevance | Cancer, ischemia-reperfusion injury, diabetic kidney disease, neonatal sepsis |
What Is GO:1903573?
GO:1903573, negative regulation of response to endoplasmic reticulum stress, is defined by QuickGO as any process that stops, prevents or reduces the frequency, rate or extent of a response to endoplasmic reticulum stress. In other words, it encompasses molecular events that suppress, delay or terminate the cellular reaction to ER stress, including inhibition of UPR signaling, enhancement of ERAD, or restoration of ER homeostasis.
Why Is negative regulation of response to endoplasmic reticulum stress Important in Cell Biology?
Negative regulation of the ER stress response is essential for maintaining cellular homeostasis and preventing chronic UPR activation, which can lead to apoptosis, inflammation or metabolic dysfunction. This process is particularly important in secretory tissues and tumors, where ER stress is common and must be tightly controlled to support survival or induce cell death as appropriate.
• Prevents excessive or prolonged UPR signaling that can trigger apoptosis and tissue damage.
• Supports cancer cell survival under hypoxia and nutrient stress by limiting ER stress-induced death.
• Protects against ischemia-reperfusion injury in liver and kidney by reducing ER stress-mediated apoptosis.
• Modulates innate immunity through ERAD control of STING pool size.
• Contributes to metabolic homeostasis in diabetic kidney disease and diabetes.
• Influences grain quality and yield under heat stress in rice, showing cross-species importance.
• Plays a role in septic neonatal foals, linking ER stress regulation to systemic inflammation.
• Provides therapeutic targets for modulating cell fate in cancer and degenerative diseases.
• Helps maintain protein secretion capacity in professional secretory cells.
• Is a key node for CRISPR-based functional genomics and drug discovery.
What Happens During negative regulation of response to endoplasmic reticulum stress?
Initiation of ER stress and UPR activation
In simple terms: When proteins misfold in the ER, cells turn on a stress alarm called the UPR.
ER stress occurs when the folding capacity of the ER is exceeded, leading to activation of three main sensors: IRE1α, PERK and ATF6. This activation initiates the unfolded protein response (UPR), which aims to restore homeostasis by increasing chaperones, expanding the ER, and enhancing ERAD. Negative regulation of this response begins when these sensors are attenuated or when their downstream targets are degraded.
ER-associated degradation (ERAD) and substrate clearance
In simple terms: The cell tags misfolded proteins for destruction to reduce ER stress.
The SEL1L-HRD1 ERAD complex recognizes misfolded proteins and targets them for ubiquitination and proteasomal degradation. This reduces the load of misfolded proteins, thereby dampening UPR signaling. GRINA enhances HRD1-mediated ubiquitination of ATF6, promoting its degradation and reducing ER stress responses in hepatic ischemia-reperfusion injury.
Attenuation of UPR signaling
In simple terms: The stress alarm is turned down once the problem is fixed.
IRE1α activity can be silenced by mechanisms that prevent sustained signaling; for example, IRE1α silences double-stranded RNA to prevent taxane-induced pyroptosis in triple-negative breast cancer, effectively limiting ER stress-induced cell death. ATF6 ubiquitination and degradation by HRD1 also attenuates UPR target gene expression. These events collectively reduce the frequency and extent of ER stress responses.
Autophagy and ER-phagy in negative regulation
In simple terms: Cells can digest parts of the ER to lower stress.
GSTK1 and RETREG1/FAM134B-mediated reticulophagy (ER-phagy) attenuates tubular injury in diabetic nephropathy by reducing ER stress and apoptosis. This autophagic clearance of ER fragments represents a negative regulatory mechanism that limits ER stress responses.
Cross-talk with other stress pathways
In simple terms: ER stress regulation is connected to mitochondrial and immune stress responses.
ATF5 regulates tubulointerstitial injury in diabetic kidney disease via the mitochondrial unfolded protein response, indicating cross-talk between ER and mitochondrial stress pathways. ER stress-related super-enhancers suppress cuproptosis via glycolysis reprogramming in lung adenocarcinoma, showing metabolic integration. SEL1L-HRD1 ERAD controls STING-mediated innate immunity by limiting the activable STING pool, linking ER stress regulation to immune signaling.
Key Genes Involved in GO:1903573 negative regulation of response to endoplasmic reticulum stress
The following genes and proteins are experimentally implicated in negative regulation of response to endoplasmic reticulum stress, based on verified PubMed literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IRE1α (ERN1) | ER stress sensor; its silencing prevents taxane-induced pyroptosis in TNBC | Target for cancer therapy and ER stress modulation |
| GRINA | Enhances HRD1-mediated ATF6 ubiquitination, reducing ER stress in liver IRI | Protective factor in ischemia-reperfusion injury |
| HRD1 (SYVN1) | E3 ubiquitin ligase in ERAD; ubiquitinates ATF6 | Core ERAD component for negative regulation |
| SEL1L | ERAD adaptor; controls STING pool and innate immunity | Links ER stress regulation to immunity |
| ATF6 | UPR transcription factor; its degradation reduces ER stress response | Substrate of HRD1-mediated negative regulation |
| GSTK1 | Mediates reticulophagy and attenuates diabetic nephropathy | Potential therapeutic target in kidney disease |
| RETREG1/FAM134B | ER-phagy receptor; reduces ER stress and apoptosis | Autophagy-related negative regulator |
| ATF5 | Regulates mitochondrial UPR in diabetic kidney disease | Cross-talk between ER and mitochondrial stress |
| STING (TMEM173) | Immune signaling controlled by ERAD | Innate immunity and ER stress intersection |
| XBP1 | UPR transcription factor downstream of IRE1α | Modulates ER stress response duration |
| PERK (EIF2AK3) | UPR sensor; its attenuation reduces ER stress signaling | Target for modulating translation under stress |
| CHOP (DDIT3) | Pro-apoptotic UPR factor; negative regulation reduces its expression | Marker of ER stress-induced apoptosis |
| BiP (HSPA5) | ER chaperone; overexpression can reduce ER stress | Indicator of ER stress levels |
| EDEM1 | ERAD component for misfolded protein clearance | Enhances negative regulation of ER stress |
| OS9 | ERAD lectin for substrate recognition | ERAD-mediated negative regulation |
| Derlin-1 (DERL1) | ERAD channel component | ER stress attenuation |
| VCP/p97 | AAA-ATPase in ERAD | Retrotranslocation of ERAD substrates |
How Is negative regulation of response to endoplasmic reticulum stress Regulated?
Negative regulation of the ER stress response is itself tightly regulated at multiple levels. The SEL1L-HRD1 ERAD complex controls the stability of ATF6 and STING, thereby limiting UPR and immune signaling. IRE1α activity can be modulated by its own silencing of dsRNA, which prevents excessive pyroptosis. Autophagy pathways, including GSTK1- and RETREG1/FAM134B-mediated reticulophagy, degrade ER fragments to reduce stress. Additionally, cross-talk with mitochondrial UPR via ATF5 influences tubulointerstitial injury. These regulatory layers ensure that ER stress responses are transient and context-appropriate.
negative regulation of response to endoplasmic reticulum stress and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IRE1α (ERN1) | Triple-negative breast cancer; taxane resistance | Knockout or point-mutation in TNBC cell lines |
| GRINA | Hepatic ischemia-reperfusion injury | Liver-specific knockout or overexpression in mice |
| GSTK1 / RETREG1 | Diabetic nephropathy; tubular injury | Kidney tubular cell knockout or knock-in |
| SEL1L / HRD1 | Innate immunity; STING-mediated inflammation | Macrophage-specific knockout |
| ATF5 | Diabetic kidney disease; tubulointerstitial injury | Kidney tubule-specific knockout or overexpression |
Cancer
In triple-negative breast cancer, IRE1α silences dsRNA to prevent taxane-induced pyroptosis, indicating that negative regulation of ER stress promotes chemoresistance. ER stress-related super-enhancers suppress cuproptosis via glycolysis reprogramming in lung adenocarcinoma, further linking negative regulation to tumor survival. Targeting these mechanisms could sensitize tumors to therapy.
Ischemia-reperfusion injury and kidney disease
GRINA alleviates hepatic ischemia-reperfusion injury by enhancing HRD1-mediated ATF6 ubiquitination, reducing ER stress and apoptosis. In diabetic nephropathy, GSTK1 and RETREG1/FAM134B-mediated reticulophagy attenuates tubular injury through ER stress and apoptosis. ATF5 regulates tubulointerstitial injury via mitochondrial UPR, highlighting cross-organelle stress regulation.
Infectious and inflammatory diseases
SEL1L-HRD1 ERAD controls STING-mediated innate immunity by limiting the activable STING pool, connecting ER stress regulation to immune responses. In septic neonatal foals, ER stress-associated genes are dysregulated, suggesting a role for negative regulation in systemic inflammation.
Metabolic and agricultural relevance
A natural gene on-off system confers field thermotolerance for grain quality and yield in rice, demonstrating that negative regulation of ER stress responses can impact crop performance under heat stress. This highlights the broad biological importance of GO:1903573 beyond human disease.
From negative regulation of response to endoplasmic reticulum stress-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene enhance ER stress response? | CRISPR knockout cell line or mouse model |
| Does a specific point mutation in a regulator alter its function? | Point-mutation knock-in via CRISPR |
| Does tagging a protein affect its localization during ER stress? | Tagged knock-in (e.g., GFP, HA) |
| Does overexpression of a regulator protect against ER stress? | Overexpression cell line or transgenic model |
| Which genes are essential for negative regulation? | CRISPR library screening |
| How does ER stress regulation change in disease? | Patient-derived organoids or disease models |
How to Study the negative regulation of response to endoplasmic reticulum stress Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcript changes | Identify UPR target genes affected by regulators |
| Proteomics | Protein abundance and modifications | Detect ERAD substrate degradation |
| Western blot | Protein levels of CHOP, BiP, ATF6, XBP1s | Quantify ER stress response |
| Luciferase reporter | UPR element activity | Screen for negative regulators |
| Immunofluorescence | Protein localization and ER morphology | Visualize ER-phagy and ERAD |
| CRISPR knockout screen | Gene essentiality for ER stress regulation | Discover novel negative regulators |
| Co-immunoprecipitation | Protein-protein interactions | Map ERAD complex components |
| qPCR | mRNA levels of UPR genes | Validate transcriptomic findings |
Transcriptomic and proteomic profiling
RNA-seq and proteomics can identify global changes in UPR target genes and ERAD components upon perturbation of candidate regulators. For example, ER stress-related super-enhancers were mapped using chromatin and transcriptomic data in lung adenocarcinoma.
Functional assays for ER stress
Luciferase reporters driven by UPR elements (e.g., CHOP, BiP promoters) and Western blotting for CHOP, BiP, ATF6 and XBP1s are standard to measure ER stress response strength.
Imaging and localization
Fluorescence microscopy with tagged ER proteins (e.g., GFP-ATF6, mCherry-SEL1L) can visualize trafficking and degradation events during negative regulation.
CRISPR screening and bioinformatics
Genome-wide CRISPR knockout or activation screens coupled with ER stress reporters can identify negative regulators of the ER stress response. Bioinformatics integration of QuickGO annotations and pathway databases helps prioritize candidates.
How CRISPR Can Be Used to Study GO:1903573 negative regulation of response to endoplasmic reticulum stress
Knockout
CRISPR knockout of candidate genes such as IRE1α, GRINA, or SEL1L can reveal whether they are required for negative regulation of ER stress. For example, IRE1α knockout in TNBC cells increases taxane-induced pyroptosis, confirming its role in limiting ER stress-induced cell death.
Point Mutation
Point mutations can dissect specific domains or phosphorylation sites. For instance, mutating the ubiquitination site on ATF6 can prevent HRD1-mediated degradation, altering negative regulation. Such models help distinguish catalytic versus scaffolding functions.
Knock-in
Knock-in of tagged versions (e.g., GFP, HA, or luciferase) allows real-time tracking of protein localization and stability during ER stress. Knock-in of disease-associated variants can model human mutations affecting ER stress regulation.
Overexpression
Overexpression of negative regulators like GRINA or GSTK1 can protect against ER stress-induced apoptosis in disease models. Conversely, overexpression of dominant-negative mutants can block negative regulation and exacerbate ER stress.
How EDITGENE Supports negative regulation of response to endoplasmic reticulum stress Research
Researchers studying negative regulation of response to endoplasmic reticulum stress-related genes often need to determine whether a candidate gene is causally involved in suppressing ER stress responses or is merely a bystander. CRISPR-based models provide the gold standard for establishing causality, and EDITGENE offers comprehensive services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of response to endoplasmic reticulum stress research.
Frequently Asked Questions About negative regulation of response to endoplasmic reticulum stress
What is GO:1903573?
GO:1903573 is the Gene Ontology term for negative regulation of response to endoplasmic reticulum stress, defined as any process that stops, prevents or reduces the frequency, rate or extent of a response to ER stress.
What genes are involved in negative regulation of ER stress?
Key genes include IRE1α, GRINA, HRD1, SEL1L, ATF6, GSTK1, RETREG1/FAM134B, ATF5 and STING.
How does negative regulation of ER stress affect cancer?
It can promote tumor survival and chemoresistance, as shown by IRE1α silencing dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
What is the role of ERAD in negative regulation of ER stress?
ERAD, mediated by SEL1L-HRD1, degrades misfolded proteins and signaling components like ATF6 and STING, thereby reducing ER stress responses.
Can CRISPR be used to study negative regulation of ER stress?
Yes, CRISPR knockout, point mutation, knock-in and overexpression models are widely used to dissect causal roles of ER stress regulators.
What diseases are linked to negative regulation of ER stress?
Cancer, hepatic ischemia-reperfusion injury, diabetic nephropathy, innate immune disorders and septic neonatal foals.
What is the difference between ER stress response and negative regulation of ER stress response?
The ER stress response activates UPR signaling; negative regulation suppresses or terminates that response.
Which proteins are sensors of ER stress?
IRE1α, PERK and ATF6 are the three main ER stress sensors.
How is negative regulation of ER stress measured experimentally?
Common methods include UPR luciferase reporters, Western blot for CHOP/BiP, RNA-seq and proteomics.
What model systems are used to study GO:1903573?
Cell lines, mouse models, patient-derived organoids and even rice for agricultural relevance.
Conclusion
GO:1903573, negative regulation of response to endoplasmic reticulum stress, is a critical biological process that restrains UPR signaling and maintains cellular homeostasis. Key regulators such as IRE1α, GRINA, SEL1L-HRD1, GSTK1 and RETREG1/FAM134B control this process through ERAD, autophagy and protein degradation. Dysregulation contributes to cancer, ischemia-reperfusion injury, kidney disease and immune disorders. CRISPR-based models are indispensable for establishing causality and developing therapeutic strategies targeting this pathway.
References
- 1. Xu L et al.. 2024. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.. Cell 187(25):7248-7266.e34 PMID: 39419025
- 2. Yu H et al.. 2025. GRINA alleviates hepatic ischemia‒reperfusion injury-induced apoptosis and ER-phagy by enhancing HRD1-mediated ATF6 ubiquitination.. J Hepatol 83(1):131-145 PMID: 39855351
- 3. Li W et al.. 2025. A natural gene on-off system confers field thermotolerance for grain quality and yield in rice.. Cell 188(14):3661-3678.e21 PMID: 40311617
- 4. Gu Y et al.. 2025. Endoplasmic reticulum stress related super-enhancers suppress cuproptosis via glycolysis reprogramming in lung adenocarcinoma.. Cell Death Dis 16(1):316 PMID: 40253387
- 5. Zhang S et al.. 2025. GSTK1 and RETREG1/FAM134B-mediated reticulophagy attenuates tubular injury in diabetic nephropathy through endoplasmic reticulum stress and apoptosis.. Autophagy 21(12):2826-2841 PMID: 40778749
- 6. Ji Y et al.. 2023. SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool.. Nat Cell Biol 25(5):726-739 PMID: 37142791
- 7. Liu Y et al.. 2023. ATF5 regulates tubulointerstitial injury in diabetic kidney disease via mitochondrial unfolded protein response.. Mol Med 29(1):57 PMID: 37095454
- 8. Sahoo DK et al.. 2025. Role of Endoplasmic Reticulum Stress-Associated Genes in Septic Neonatal Foals.. Antioxidants (Basel) 14(8) PMID: 40867920
