GO:1904293 negative regulation of ERAD pathway: Protein Quality Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904293 (negative regulation of ERAD pathway) describes any process that stops, prevents, or reduces the frequency, rate, or extent of endoplasmic reticulum-associated degradation (ERAD).
• ERAD is a conserved protein quality-control pathway that removes misfolded or unneeded proteins from the ER, and its negative regulation is critical for tuning protein homeostasis.
• Key negative regulators include sigma-1 receptor (SIGMAR1), which promotes ERAD of specific substrates such as SERCA2 and UDP-galactose:ceramide galactosyltransferase.
• Dysregulation of ERAD negative regulation is linked to cancer progression, innate immunity, and viral glycoprotein expression.
• Experimental models for studying GO:1904293 include CRISPR knockout, point mutation, knock-in, and overexpression cell lines, combined with proteomics and imaging.
• EDITGENE provides CRISPR services to dissect negative regulation of ERAD pathway, enabling target validation and drug discovery.
Description
The Gene Ontology term GO:1904293, negative regulation of ERAD pathway, refers to any process that stops, prevents, or reduces the frequency, rate, or extent of endoplasmic reticulum-associated degradation (ERAD). ERAD is a major protein quality-control system in the endoplasmic reticulum (ER) that targets misfolded or regulated proteins for ubiquitination and proteasomal degradation. Negative regulation of this pathway is essential for maintaining ER homeostasis, allowing cells to adapt to stress and to preserve proteins that are required for specific physiological functions. Researchers study this term because its dysregulation contributes to cancer, immune disorders, and viral infections, and because it offers therapeutic targets for modulating protein degradation. Understanding the molecular players and mechanisms of ERAD negative regulation is therefore of broad biomedical importance.
negative regulation of ERAD pathway At A Glance
| GO ID | GO:1904293 |
|---|---|
| GO term | negative regulation of ERAD pathway |
| Ontology | biological_process |
| Synonym | down regulation of endoplasmic reticulum-associated degradation; inhibition of ERAD pathway; negative regulation of ER-associated degradation pathway |
| Major function | Stops, prevents, or reduces the frequency, rate, or extent of ERAD pathway |
| Related pathway | ERAD (endoplasmic reticulum-associated degradation) |
| Key regulators | SIGMAR1, SEL1L-HRD1, EDEM1, EMC2, UBXN6, PDIs |
| Disease relevance | Cancer, innate immunity, viral infection, osteoclastogenesis |
What Is GO:1904293?
GO:1904293 is defined as any biological process that stops, prevents, or reduces the frequency, rate, or extent of the ERAD pathway. In other words, it encompasses molecular events that inhibit the recognition, ubiquitination, retrotranslocation, or degradation of ER proteins, thereby slowing or blocking ERAD. This regulation can occur through direct interaction with ERAD components, modulation of substrate stability, or changes in the expression of ERAD machinery.
Why Is negative regulation of ERAD pathway Important in Cell Biology?
Negative regulation of ERAD pathway is important because it fine-tunes protein degradation to prevent excessive loss of functional proteins and to allow cells to respond to physiological demands. For example, sigma-1 receptor (SIGMAR1) negatively regulates ERAD of SERCA2 in osteoclasts, thereby attenuating osteoclastogenesis. Similarly, SEL1L-HRD1 ERAD controls STING-mediated innate immunity by limiting the activable STING pool, and its negative regulation can modulate immune responses. In cancer, EDEM1 accelerates ERAD and activates Keap1/Nrf2 to induce doxorubicin resistance in triple-negative breast cancer, highlighting the therapeutic relevance of ERAD regulation. Thus, understanding GO:1904293 provides insights into disease mechanisms and potential drug targets.
• Modulates ER protein homeostasis and prevents excessive degradation of functional proteins.
• Regulates innate immunity by controlling the STING pool through SEL1L-HRD1 ERAD.
• Influences cancer cell survival and drug resistance, as seen with EDEM1 in triple-negative breast cancer.
• Affects osteoclastogenesis via SIGMAR1-mediated ERAD of SERCA2.
• Controls viral glycoprotein expression, as PDIs negatively regulate ebolavirus glycoprotein via autophagy-lysosomal pathway.
• Impacts ferroptosis susceptibility through EMC2 protection of FDFT1 from ERAD.
• Regulates autophagy and inflammation in macrophages via UBXN6.
• Provides targets for therapeutic intervention in cancer, immune disorders, and infections.
What Happens During negative regulation of ERAD pathway?
Recognition of ERAD substrates and its inhibition
In simple terms: Cells normally tag misfolded proteins for destruction, but negative regulation can block this tagging step.
ERAD begins with recognition of misfolded or regulated proteins by chaperones and lectins such as EDEM1. Negative regulation can occur when factors like SIGMAR1 interact with specific substrates, preventing their recognition or recruitment to the ERAD machinery. For instance, SIGMAR1 promotes ER-associated degradation of SERCA2, but its negative regulation of ERAD for other substrates may involve stabilization of the substrate. This step is critical for determining which proteins are spared from degradation.
Ubiquitination and retrotranslocation control
In simple terms: Negative regulation can stop the addition of ubiquitin tags or the movement of proteins out of the ER.
Ubiquitination of ERAD substrates is mediated by E3 ligases such as HRD1, and retrotranslocation moves them to the cytosol for proteasomal degradation. Negative regulation of ERAD can inhibit these steps; for example, SEL1L-HRD1 complex controls STING degradation, and its negative regulation limits the size of the activable STING pool. UBXN6 is essential for autophagy induction and inflammation control, and it may influence ERAD-related degradation pathways. PDIs negatively regulate ebolavirus glycoprotein expression by diverting it to autophagy-lysosomal degradation, illustrating a form of ERAD negative regulation.
Proteasomal degradation and its modulation
In simple terms: Even if a protein is tagged, negative regulation can prevent its final destruction by the proteasome.
The final step of ERAD is proteasomal degradation of retrotranslocated substrates. Negative regulation can occur through factors that stabilize substrates or inhibit proteasome recruitment. For example, EMC2 protects FDFT1 from ERAD to impair ferroptosis susceptibility in triple-negative breast cancer, effectively negatively regulating ERAD of FDFT1. Similarly, TRIM25 promotes cell survival by targeting Keap1-Nrf2 pathway, which may involve modulation of ERAD. These examples show that negative regulation at the degradation step can have profound effects on cell fate.
Cross-talk with autophagy and lysosomal pathways
In simple terms: Negative regulation of ERAD can redirect proteins to other degradation routes like autophagy.
ERAD and autophagy are interconnected quality-control systems. Negative regulation of ERAD may involve shunting substrates to autophagy-lysosomal degradation, as seen with PDIs and ebolavirus glycoprotein. UBXN6 is essential for autophagy induction and inflammation control in macrophages, suggesting a link between ERAD regulation and autophagy. This cross-talk ensures cellular adaptation under stress.
Regulation of ERAD machinery expression
In simple terms: Cells can reduce ERAD by making less of its components.
Negative regulation of ERAD can also occur at the transcriptional or translational level, reducing the abundance of ERAD components such as EDEM1 or HRD1. For instance, EDEM1 expression levels influence ERAD activity and doxorubicin resistance in breast cancer. SEL1L-HRD1 levels affect STING turnover and innate immunity. Thus, controlling ERAD machinery expression is a key mechanism of negative regulation.
Key Genes Involved in GO:1904293 negative regulation of ERAD pathway
The following genes and proteins are experimentally implicated in negative regulation of ERAD pathway or its modulation, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SIGMAR1 | Promotes ERAD of SERCA2; negative regulation of ERAD for specific substrates | Osteoclastogenesis, ER chaperone function |
| SEL1L | Component of SEL1L-HRD1 ERAD complex; controls STING pool | Innate immunity, ERAD regulation |
| HRD1 (SYVN1) | E3 ubiquitin ligase in ERAD; targets STING | ERAD, immune regulation |
| EDEM1 | Accelerates ERAD; activates Keap1/Nrf2 | Doxorubicin resistance in TNBC |
| EMC2 | Protects FDFT1 from ERAD; impairs ferroptosis | Triple negative breast cancer growth |
| UBXN6 | Essential for autophagy induction and inflammation control | Macrophage inflammation, autophagy |
| PDIs | Negatively regulate ebolavirus glycoprotein via autophagy-lysosomal pathway | Viral glycoprotein expression |
| TRIM25 | Promotes cell survival via Keap1-Nrf2; may modulate ERAD | Hepatocellular carcinoma |
| SERCA2 (ATP2A2) | Substrate of SIGMAR1-mediated ERAD | Osteoclastogenesis |
| STING (TMEM173) | Substrate of SEL1L-HRD1 ERAD | Innate immunity |
| Keap1 | Target of TRIM25; Nrf2 pathway | Cancer cell survival |
| Nrf2 (NFE2L2) | Antioxidant pathway activated by EDEM1 | Doxorubicin resistance |
| FDFT1 | Protected from ERAD by EMC2 | Ferroptosis susceptibility |
| UDP-galactose:ceramide galactosyltransferase (UGT8) | Lifetime controlled by ERAD regulated by sigma-1 receptor | ERAD regulation |
| EBOV GP | Ebolavirus glycoprotein negatively regulated by PDIs | Viral infection |
| ATG proteins | Autophagy machinery linked to UBXN6 | Inflammation control |
How Is negative regulation of ERAD pathway Regulated?
Negative regulation of ERAD pathway is itself regulated by various cellular signals. For example, sigma-1 receptor chaperones control the lifetime of UDP-galactose:ceramide galactosyltransferase through a distinct ERAD pathway. SEL1L-HRD1 ERAD controls STING-mediated innate immunity by limiting the activable STING pool, and this regulation is critical for immune homeostasis. In cancer, EDEM1 accelerates ERAD and activates Keap1/Nrf2 antioxidant pathway, which can be modulated by chemotherapeutic stress. UBXN6 is essential for autophagy induction and inflammation control in macrophages, linking ERAD regulation to inflammatory signaling. These examples illustrate that negative regulation of ERAD is integrated with chaperone networks, immune signaling, and stress responses.
negative regulation of ERAD pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| EDEM1 | Doxorubicin resistance in triple-negative breast cancer | Knockout or overexpression in TNBC cell lines |
| EMC2 | Triple negative breast cancer growth and ferroptosis | Knockout in TNBC cells |
| SEL1L/HRD1 | STING-mediated innate immunity | Knockout in immune cells |
| SIGMAR1 | Osteoclastogenesis | Knockout in osteoclast precursors |
| UBXN6 | Macrophage inflammation and autophagy | Knockout in macrophages |
Cancer
Negative regulation of ERAD pathway is implicated in cancer progression and drug resistance. EDEM1 inhibits ER stress to induce doxorubicin resistance through accelerating ERAD and activating Keap1/Nrf2 antioxidant pathway in triple-negative breast cancer. EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from ERAD to impair ferroptosis susceptibility. TRIM25 promotes cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway, which may involve ERAD modulation. These findings suggest that targeting ERAD negative regulation could overcome chemoresistance.
Innate immunity and inflammation
SEL1L-HRD1 ERAD controls STING-mediated innate immunity by limiting the size of the activable STING pool, and its negative regulation can dampen immune responses. UBXN6 is essential for autophagy induction and inflammation control in macrophages, linking ERAD regulation to inflammatory diseases. Dysregulation of these pathways may contribute to autoimmunity or immunodeficiency.
Bone metabolism
Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2, indicating that negative regulation of ERAD for specific substrates can influence bone homeostasis. Modulation of SIGMAR1 activity may affect osteoclast differentiation and bone diseases.
Viral infection
Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the ER via the autophagy-lysosomal pathway, highlighting a role for ERAD-related negative regulation in viral replication. Understanding these mechanisms may inform antiviral strategies.
From negative regulation of ERAD pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SIGMAR1 negatively regulate ERAD of SERCA2? | SIGMAR1 knockout and overexpression in osteoclasts |
| How does SEL1L-HRD1 control STING pool? | SEL1L or HRD1 knockout in immune cells |
| Does EDEM1 accelerate ERAD and induce doxorubicin resistance? | EDEM1 knockout/overexpression in TNBC cells |
| Does EMC2 protect FDFT1 from ERAD? | EMC2 knockout in TNBC cells |
| Is UBXN6 essential for autophagy and inflammation? | UBXN6 knockout in macrophages |
| Do PDIs negatively regulate ebolavirus glycoprotein? | PDI knockout/overexpression in viral infection models |
How to Study the negative regulation of ERAD pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Gene essentiality for ERAD regulation | Identify negative regulators |
| Proteomics | Protein abundance and interactions | Quantify ERAD substrates |
| Imaging | Subcellular localization and degradation | Track ERAD of SERCA2 or STING |
| RNA-seq | Transcriptional changes | Measure EDEM1 and Nrf2 targets |
| Flow cytometry | Protein levels on cell surface | STING pool size |
| Western blot | Protein stability and ubiquitination | ERAD substrate turnover |
| Immunoprecipitation | Protein-protein interactions | SIGMAR1-SERCA2 interaction |
| Autophagy flux assay | Autophagic degradation | UBXN6 and PDIs |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify genes whose loss alters ERAD activity or negative regulation. For example, knocking out SIGMAR1, SEL1L, or EDEM1 can reveal their roles in ERAD regulation. These screens are powerful for discovering novel negative regulators.
Proteomics and interactomics
Mass spectrometry-based proteomics can quantify ERAD substrate levels and identify interaction partners of ERAD components. Studies on SEL1L-HRD1 and STING used proteomic approaches to show regulation of STING pool. Similarly, EMC2-FDFT1 interaction was studied by proteomics.
Imaging and flow cytometry
Fluorescence microscopy and flow cytometry can track ERAD substrate degradation and ER morphology. For instance, SIGMAR1-mediated ERAD of SERCA2 was visualized in osteoclasts. STING trafficking was monitored by imaging.
RNA-seq and transcriptomics
RNA sequencing can reveal transcriptional changes in ERAD machinery upon negative regulation. EDEM1 expression and Keap1/Nrf2 pathway activation were studied by transcriptomics in breast cancer. UBXN6-dependent autophagy genes were analyzed by RNA-seq.
How CRISPR Can Be Used to Study GO:1904293 negative regulation of ERAD pathway
Knockout
CRISPR knockout of genes such as SIGMAR1, SEL1L, HRD1, EDEM1, EMC2, or UBXN6 can abolish their negative regulation of ERAD, leading to increased ERAD activity and altered substrate levels. These models are essential for validating gene function in ERAD regulation.
Point Mutation
Point mutations can be introduced to disrupt specific domains or catalytic residues of ERAD regulators. For example, mutating the E3 ligase domain of HRD1 or the chaperone activity of SIGMAR1 can reveal domain-specific functions in negative regulation of ERAD. Such models help dissect molecular mechanisms.
Knock-in
Knock-in of tagged versions (e.g., GFP, HA) of ERAD components allows tracking of their localization and interactions. Tagged SEL1L or EDEM1 can be used to monitor ERAD complex dynamics. Knock-in of disease-associated mutations can model human disorders.
Overexpression
Overexpression of negative regulators such as SIGMAR1, EDEM1, or EMC2 can suppress ERAD and stabilize specific substrates, mimicking disease states like cancer drug resistance. These models are useful for drug screening.
How EDITGENE Supports negative regulation of ERAD pathway Research
Researchers studying negative regulation of ERAD pathway-related genes often need to determine whether a candidate gene is causally involved in ERAD regulation or is merely correlated with changes in protein degradation. EDITGENE provides CRISPR-based cell model services to enable precise genetic perturbations and functional validation.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of ERAD pathway research.
Frequently Asked Questions About negative regulation of ERAD pathway
What is GO:1904293?
GO:1904293 is the Gene Ontology term for negative regulation of ERAD pathway, defined as any process that stops, prevents, or reduces the frequency, rate, or extent of ERAD pathway.
What genes are involved in negative regulation of ERAD pathway?
Key genes include SIGMAR1, SEL1L, HRD1, EDEM1, EMC2, UBXN6, and PDIs, as shown in studies on ERAD regulation.
How does negative regulation of ERAD affect cancer?
It can promote drug resistance and tumor growth; for example, EDEM1 induces doxorubicin resistance in triple-negative breast cancer, and EMC2 protects FDFT1 from ERAD to impair ferroptosis.
What is the role of SIGMAR1 in ERAD?
SIGMAR1 promotes ER-associated degradation of SERCA2 and controls the lifetime of UDP-galactose:ceramide galactosyltransferase, acting as a negative regulator of ERAD for specific substrates.
How is ERAD negatively regulated in immunity?
SEL1L-HRD1 ERAD controls STING-mediated innate immunity by limiting the activable STING pool, and its negative regulation modulates immune responses.
What experimental models are used to study negative regulation of ERAD?
CRISPR knockout, point mutation, knock-in, and overexpression cell models are commonly used, along with proteomics and imaging.
Which diseases are linked to negative regulation of ERAD pathway?
Cancer, innate immunity disorders, bone metabolism disorders, and viral infections are linked to dysregulation of ERAD negative regulation.
How does UBXN6 relate to ERAD?
UBXN6 is essential for autophagy induction and inflammation control in macrophages, linking ERAD regulation to autophagy and inflammation.
Can CRISPR screens identify negative regulators of ERAD?
Yes, genome-wide CRISPR knockout screens can identify genes whose loss alters ERAD activity, revealing novel negative regulators.
What services does EDITGENE offer for ERAD research?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression cell models, library screening, and bioinformatics services for ERAD pathway research.
Conclusion
GO:1904293 negative regulation of ERAD pathway is a critical biological process that fine-tunes protein degradation in the ER, with profound implications for cancer, immunity, bone metabolism, and viral infection. Understanding its molecular players and mechanisms provides opportunities for therapeutic intervention. EDITGENE offers comprehensive CRISPR services to accelerate research on this pathway.
References
- 1. Wei X et al.. 2022. Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2.. EMBO Mol Med 14(7):e15373 PMID: 35611810
- 2. Liu Y et al.. 2020. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway.. Nat Commun 11(1):348 PMID: 31953436
- 3. 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
- 4. Wang Y et al.. 2025. EDEM1 Inhibits Endoplasmic Reticulum Stress to Induce Doxorubicin Resistance through Accelerating ERAD and Activating Keap1/Nrf2 Antioxidant Pathway in Triple-Negative Breast Cancer.. Research (Wash D C) 8:0797 PMID: 40735463
- 5. Kim YJ et al.. 2024. Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages.. Cell Mol Immunol 21(12):1441-1458 PMID: 39438692
- 6. Dong X et al.. 2025. EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from endoplasmic reticulum associated degradation to impair ferroptosis susceptibility.. Oncogene 44(39):3713-3728 PMID: 40931051
- 7. Wang B et al.. 2022. Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.. Autophagy 18(10):2350-2367 PMID: 35130104
- 8. Hayashi T et al.. 2012. The lifetime of UDP-galactose:ceramide galactosyltransferase is controlled by a distinct endoplasmic reticulum-associated degradation (ERAD) regulated by sigma-1 receptor chaperones.. J Biol Chem 287(51):43156-69 PMID: 23105111
