GO:1904828 positive regulation of hydrogen sulfide biosynthetic process: Regulation, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904828 describes any process that activates or increases the frequency, rate or extent of hydrogen sulfide (H2S) biosynthetic process [1,2].
• Hydrogen sulfide is a gasotransmitter synthesized mainly by CBS, CSE, and MPST, and its production is tightly regulated at transcriptional and post-translational levels [3,5,6].
• Positive regulation of H2S biosynthesis impacts diverse physiological and pathological processes, including ferroptosis, autophagy, inflammation, and cancer [1,4,5,8].
• Key regulators include ATF3, ATF4, TFEB, AMPKα1, and the CRL3(KCTD10)-USP18 axis, which modulate H2S-producing enzymes or downstream targets [1,4,5,7,8].
• Dysregulation of H2S biosynthesis is linked to colorectal cancer, glioblastoma, inflammatory bowel disease, atherosclerosis, and metabolic disorders [3,5,6,7,8].
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are essential to dissect causal roles of genes in the positive regulation of H2S biosynthesis [1,3,4,5,7,8].
Description
Hydrogen sulfide (H2S) is a gaseous signaling molecule that regulates a wide range of biological processes, including vascular tone, neurotransmission, inflammation, and cell survival [2,5,6]. The biosynthetic process of H2S is primarily mediated by three enzymes: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MPST) [3,5,6]. The Gene Ontology term GO:1904828, positive regulation of hydrogen sulfide biosynthetic process, refers to any process that activates or increases the frequency, rate or extent of H2S biosynthesis [1,2]. Understanding this regulatory node is critical because H2S levels are altered in numerous diseases, and manipulating its production offers therapeutic potential [3,5,6,8]. Recent studies have identified multiple regulators that enhance H2S biosynthesis or compensate for its loss. For example, ATF4 induces SLC7A11 (xCT) to block stress-related ferroptosis, indirectly influencing H2S availability. The CRL3(KCTD10) ubiquitin ligase-USP18 axis regulates cystine uptake and ferroptosis by modulating SLC7A11, which intersects with H2S metabolism. In vascular smooth muscle cells, TFEB-mediated autophagy promotes H2S production and atherosclerotic plaque stability. Additionally, AMPKα1-mediated ZDHHC8 phosphorylation enhances SLC7A11 palmitoylation, contributing to ferroptosis resistance in glioblastoma. These findings highlight the intricate crosstalk between H2S biosynthesis and cellular stress responses. This article provides a research-grade overview of GO:1904828, covering its definition, key genes, regulatory mechanisms, disease associations, and experimental models. It is designed for researchers seeking to understand how positive regulation of H2S biosynthesis is achieved and how to study it using CRISPR-based tools and other methodologies.
positive regulation of hydrogen sulfide biosynthetic process At A Glance
| GO ID | GO:1904828 |
|---|---|
| GO term | positive regulation of hydrogen sulfide biosynthetic process |
| Ontology | biological_process |
| Synonym | activation of hydrogen sulfide biosynthetic process; upregulation of hydrogen sulfide biosynthesis; positive regulation of hydrogen sulfide formation |
| Major function | Upregulation of hydrogen sulfide (H2S) production |
| Related enzymes | CBS, CSE, MPST |
| Key regulators | ATF3, ATF4, TFEB, AMPKα1, CRL3(KCTD10)-USP18 |
| Associated diseases | Colorectal cancer, glioblastoma, inflammatory bowel disease, atherosclerosis |
What Is GO:1904828?
GO:1904828 is a biological process term defined as any process that activates or increases the frequency, rate or extent of hydrogen sulfide biosynthetic process. In other words, it encompasses all molecular events that upregulate the production of H2S, a gasotransmitter synthesized by enzymes such as CBS, CSE, and MPST. This term is a child of positive regulation of biosynthetic process and is distinct from negative regulation or the biosynthetic process itself.
Why Is positive regulation of hydrogen sulfide biosynthetic process Important in Cell Biology?
Positive regulation of hydrogen sulfide biosynthetic process is crucial because H2S is a pleiotropic gasotransmitter involved in cytoprotection, vasodilation, neurotransmission, and inflammation resolution [2,5,6]. Dysregulated H2S production contributes to cancer progression, cardiovascular disease, and inflammatory disorders [3,5,6,8]. Understanding how this process is positively regulated can reveal therapeutic targets and biomarkers, and it enables researchers to manipulate H2S levels experimentally to study its downstream effects.
• H2S is a gasotransmitter that regulates vascular tone, neurotransmission, and inflammation [2,5,6].
• Positive regulation of H2S biosynthesis can protect against ferroptosis by modulating SLC7A11 [1,4,7].
• ATF3-CBS signaling coordinates ferroptosis and tumorigenesis in colorectal cancer.
• MPST deficiency aggravates inflammatory bowel disease via AKT, highlighting the importance of H2S production.
• TFEB-mediated autophagy promotes H2S production and atherosclerotic plaque stability.
• H2S regulates lipid metabolism with implications for cardiovascular health.
• AMPKα1-mediated ZDHHC8 phosphorylation enhances SLC7A11 palmitoylation and ferroptosis resistance in glioblastoma.
• The CRL3(KCTD10)-USP18 axis regulates cystine uptake and ferroptosis, intersecting with H2S metabolism.
• ATF4 induces SLC7A11 to block stress-related ferroptosis, linking H2S to cellular stress responses.
• Targeting positive regulators of H2S biosynthesis may offer new therapeutic strategies for cancer and inflammatory diseases [3,5,8].
What Happens During positive regulation of hydrogen sulfide biosynthetic process?
Transcriptional upregulation of H2S-producing enzymes
In simple terms: Cells increase the production of enzymes that make hydrogen sulfide.
Positive regulation often begins with increased transcription of genes encoding CBS, CSE, and MPST. For instance, ATF3-CBS signaling axis coordinates ferroptosis and tumorigenesis in colorectal cancer, where ATF3 modulates CBS expression. Similarly, ATF4 induces SLC7A11 to block stress-related ferroptosis, indirectly supporting H2S biosynthesis. These transcriptional programs enhance the capacity for H2S synthesis under stress conditions.
Post-translational modification and enzyme stability
In simple terms: Enzymes can be chemically modified to become more active or stable.
Post-translational modifications regulate H2S-producing enzymes. The CRL3(KCTD10) ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11, which affects H2S metabolism. AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma, linking energy sensing to H2S-related pathways. These modifications can enhance enzyme activity or prevent degradation.
Autophagy-mediated regulation
In simple terms: Cellular recycling processes can boost hydrogen sulfide production.
TFEB (transcription factor EB)-mediated autophagy promotes H2S production in vascular smooth muscle cells, contributing to atherosclerotic plaque stability. This suggests that autophagy positively regulates H2S biosynthesis by providing substrates or by upregulating enzyme expression. The interplay between autophagy and H2S production is a key mechanism in cardiovascular protection.
Integration with cellular stress and metabolic signals
In simple terms: Stress and energy sensors can turn up hydrogen sulfide production.
Positive regulation of H2S biosynthesis is integrated with stress-responsive pathways. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 to block stress-related ferroptosis, which may involve H2S. MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT, indicating that H2S production is protective under inflammatory stress. Additionally, H2S regulates lipid metabolism with implications for cardiovascular health. These signals converge to fine-tune H2S levels.
Key Genes Involved in GO:1904828 positive regulation of hydrogen sulfide biosynthetic process
The following genes and proteins are central to the positive regulation of hydrogen sulfide biosynthetic process, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CBS | Enzyme that synthesizes H2S | ATF3-CBS axis in colorectal cancer |
| CSE | Enzyme that synthesizes H2S | Vascular H2S production and atherosclerosis |
| MPST | Enzyme that synthesizes H2S | MPST deficiency in inflammatory bowel disease |
| SLC7A11 | Cystine/glutamate antiporter, affects H2S metabolism | Regulated by ATF4, CRL3(KCTD10)-USP18, AMPKα1 [1,4,7] |
| ATF3 | Transcription factor regulating CBS | Coordinates ferroptosis and tumorigenesis |
| ATF4 | Transcription factor inducing SLC7A11 | Suppresses hepatocarcinogenesis |
| TFEB | Transcription factor promoting autophagy | Promotes H2S production in VSMC |
| AMPKα1 | Energy sensor kinase | Phosphorylates ZDHHC8 to regulate SLC7A11 |
| ZDHHC8 | Palmitoyltransferase | Palmitoylates SLC7A11 in glioblastoma |
| KCTD10 | Substrate receptor of CRL3 ubiquitin ligase | Regulates SLC7A11 and ferroptosis |
| USP18 | Deubiquitinase | Counteracts KCTD10-mediated regulation |
| AKT | Kinase involved in apoptosis | Mediates effects of MPST deficiency |
| CBS | H2S-producing enzyme | Target for colorectal cancer therapy |
| CSE | H2S-producing enzyme | Therapeutic target in cardiovascular disease [5,6] |
| MPST | H2S-producing enzyme | Protective in intestinal inflammation |
| SLC7A11 | Cystine transporter | Ferroptosis regulator in cancer [1,4,7] |
| TFEB | Autophagy regulator | Atherosclerotic plaque stability |
How Is positive regulation of hydrogen sulfide biosynthetic process Regulated?
The positive regulation of hydrogen sulfide biosynthetic process is controlled at multiple levels. Transcriptionally, ATF3 and ATF4 modulate CBS and SLC7A11 expression, respectively [1,8]. Post-translationally, the CRL3(KCTD10) ubiquitin ligase and USP18 deubiquitinase dynamically regulate SLC7A11 stability. AMPKα1 phosphorylates ZDHHC8, which palmitoylates SLC7A11, enhancing its function. TFEB-mediated autophagy promotes H2S production in vascular smooth muscle cells. Additionally, MPST deficiency affects AKT signaling, influencing cell survival. These regulatory layers ensure appropriate H2S levels in response to cellular stress and metabolic cues.
positive regulation of hydrogen sulfide biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CBS | Colorectal cancer | CBS knockout or overexpression in HCT116 cells |
| MPST | Inflammatory bowel disease | MPST knockout mice or intestinal epithelial cells |
| SLC7A11 | Ferroptosis in cancer | SLC7A11 knockout or point mutation in cancer cell lines [1,4,7] |
| TFEB | Atherosclerosis | TFEB knockout or overexpression in vascular smooth muscle cells |
| CSE | Cardiovascular disease | CSE knockout mice or endothelial cells [5,6] |
Cancer
Positive regulation of H2S biosynthesis is implicated in multiple cancers. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 to block stress-related ferroptosis. The CRL3(KCTD10)-USP18 axis regulates cystine uptake and ferroptosis, affecting tumor growth. AMPKα1-mediated ZDHHC8 phosphorylation promotes ferroptosis resistance in glioblastoma. ATF3-CBS signaling coordinates ferroptosis and tumorigenesis in colorectal cancer. These findings suggest that targeting H2S biosynthesis pathways could be therapeutically beneficial.
Inflammatory bowel disease
MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT, indicating that H2S production is protective in the gut. Positive regulation of H2S biosynthesis may therefore be a therapeutic strategy for inflammatory bowel disease.
Cardiovascular disease
Vascular smooth muscle cell-derived H2S promotes atherosclerotic plaque stability via TFEB-mediated autophagy. H2S also regulates lipid metabolism with implications for cardiovascular health. Enhancing H2S biosynthesis could stabilize plaques and improve cardiovascular outcomes.
From positive regulation of hydrogen sulfide biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CBS knockout affect H2S production and tumor growth? | CBS knockout cell line (e.g., HCT116) |
| Does MPST deficiency alter intestinal inflammation? | MPST knockout mouse model |
| Does point mutation in SLC7A11 affect ferroptosis? | SLC7A11 point-mutant knock-in cells [1,4,7] |
| Does TFEB overexpression increase H2S and plaque stability? | TFEB overexpression in vascular smooth muscle cells |
| Does AMPKα1-mediated ZDHHC8 phosphorylation regulate SLC7A11? | ZDHHC8 knock-in with phospho-mimetic mutation |
| Does CRL3(KCTD10) regulate SLC7A11 stability? | KCTD10 knockout or knockdown cells |
How to Study the positive regulation of hydrogen sulfide biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Gene essentiality for H2S regulation | Identify novel regulators |
| RNA-seq | Transcriptional changes | Measure CBS, CSE, MPST expression [1,8] |
| Proteomics | Protein abundance and modifications | Assess SLC7A11 palmitoylation |
| H2S detection assay | H2S concentration | Validate functional impact [3,5] |
| Autophagy flux assay | Autophagic activity | Link TFEB to H2S production |
| Ferroptosis assay | Cell death due to lipid peroxidation | Study SLC7A11 regulation [1,4,7] |
| Immunoblotting | Protein expression and phosphorylation | Check AKT signaling in MPST deficiency |
| Luciferase reporter | Promoter activity | Assess ATF3-mediated CBS transcription |
CRISPR-Cas9 knockout screens
Genome-wide CRISPR knockout screens can identify genes that positively regulate H2S biosynthesis. For example, knocking out KCTD10 or USP18 can reveal their roles in SLC7A11 regulation and ferroptosis. Such screens are powerful for discovering novel regulators.
Transcriptomics and proteomics
RNA-seq and proteomics can quantify changes in H2S-producing enzymes (CBS, CSE, MPST) and related regulators upon genetic or pharmacological perturbations [1,3,5,8]. These methods help delineate transcriptional and post-translational networks.
Metabolic assays for H2S
Direct measurement of H2S levels using colorimetric or fluorescent probes can confirm functional changes in H2S biosynthesis. Combining these assays with CRISPR models validates the impact of specific genes [3,5,6].
Imaging and autophagy flux
Live-cell imaging of autophagy markers (e.g., LC3) can assess TFEB-mediated autophagy and its effect on H2S production. This approach links cellular recycling to H2S biosynthesis.
How CRISPR Can Be Used to Study GO:1904828 positive regulation of hydrogen sulfide biosynthetic process
Knockout
CRISPR knockout of genes such as CBS, MPST, or KCTD10 can abolish or reduce H2S biosynthesis, revealing their necessity. For example, MPST knockout aggravates inflammatory bowel disease in models, and KCTD10 knockout stabilizes SLC7A11, affecting ferroptosis.
Point Mutation
Introducing point mutations (e.g., phospho-mimetic or phospho-deficient) in ZDHHC8 or SLC7A11 can dissect specific post-translational modifications. AMPKα1-mediated ZDHHC8 phosphorylation is a key regulatory event, and point mutants can test its functional relevance.
Knock-in
Knock-in of tagged versions of CBS, CSE, or MPST allows tracking of endogenous protein localization and interactions. This is useful for studying how these enzymes are regulated in response to stress [1,5].
Overexpression
Overexpression of TFEB or ATF4 can enhance H2S biosynthesis and protect against disease. For instance, TFEB overexpression promotes H2S production and plaque stability, while ATF4 induction blocks ferroptosis.
How EDITGENE Supports positive regulation of hydrogen sulfide biosynthetic process Research
Researchers studying positive regulation of hydrogen sulfide biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in H2S production, ferroptosis resistance, or disease progression. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of hydrogen sulfide biosynthetic process research.
Frequently Asked Questions About positive regulation of hydrogen sulfide biosynthetic process
What is GO:1904828?
GO:1904828 is a Gene Ontology term for any process that activates or increases the frequency, rate or extent of hydrogen sulfide biosynthetic process [1,2].
What genes are involved in positive regulation of hydrogen sulfide biosynthetic process?
Key genes include CBS, CSE, MPST, SLC7A11, ATF3, ATF4, TFEB, AMPKα1, ZDHHC8, KCTD10, and USP18 [1,3,4,5,7,8].
How is hydrogen sulfide biosynthesis regulated?
It is regulated transcriptionally (e.g., ATF3, ATF4), post-translationally (e.g., CRL3(KCTD10)-USP18, AMPKα1-ZDHHC8), and via autophagy (TFEB) [1,4,5,7,8].
What diseases are associated with hydrogen sulfide biosynthesis?
Colorectal cancer, glioblastoma, inflammatory bowel disease, atherosclerosis, and metabolic disorders [3,5,6,7,8].
What is the role of MPST in hydrogen sulfide biosynthesis?
MPST is an H2S-producing enzyme; its deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT.
How does SLC7A11 relate to hydrogen sulfide?
SLC7A11 regulates cystine uptake and ferroptosis, intersecting with H2S metabolism; it is modulated by ATF4, CRL3(KCTD10)-USP18, and AMPKα1-ZDHHC8 [1,4,7].
What is the role of TFEB in hydrogen sulfide production?
TFEB-mediated autophagy promotes H2S production in vascular smooth muscle cells, contributing to atherosclerotic plaque stability.
Can CRISPR be used to study hydrogen sulfide biosynthesis?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect gene function in H2S pathways [1,3,4,5,7,8].
What is the ATF3-CBS signaling axis?
ATF3 regulates CBS expression, coordinating ferroptosis and tumorigenesis in colorectal cancer.
How does AMPKα1 regulate hydrogen sulfide biosynthesis?
AMPKα1 phosphorylates ZDHHC8, which palmitoylates SLC7A11, enhancing ferroptosis resistance in glioblastoma.
Conclusion
GO:1904828, positive regulation of hydrogen sulfide biosynthetic process, is a critical biological process with broad implications for cancer, inflammation, and cardiovascular disease. The interplay between H2S-producing enzymes and regulators such as ATF3, ATF4, TFEB, and the CRL3(KCTD10)-USP18 axis underscores the complexity of this regulation. CRISPR-based models and multi-omics approaches are indispensable for uncovering new therapeutic targets. EDITGENE offers comprehensive services to support this research.
References
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- 2. Huang D et al.. 2023. Regulation of Mitochondrial Respiration by Hydrogen Sulfide.. Antioxidants (Basel) 12(8) PMID: 37627639
- 3. Zhang J et al.. 2022. MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT.. Redox Biol 56:102469 PMID: 36126419
- 4. Zhou Q et al.. 2024. The CRL3(KCTD10) ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11.. Proc Natl Acad Sci U S A 121(28):e2320655121 PMID: 38959043
- 5. Chen Z et al.. 2022. Vascular smooth muscle cell-derived hydrogen sulfide promotes atherosclerotic plaque stability via TFEB (transcription factor EB)-mediated autophagy.. Autophagy 18(10):2270-2287 PMID: 35090378
- 6. Flori L et al.. 2024. Role of hydrogen sulfide in the regulation of lipid metabolism: Implications on cardiovascular health.. Life Sci 341:122491 PMID: 38336275
- 7. Wang Z et al.. 2024. AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma.. Cancer Lett 584:216619 PMID: 38211651
- 8. Liu J et al.. 2024. ATF3-CBS signaling axis coordinates ferroptosis and tumorigenesis in colorectal cancer.. Redox Biol 71:103118 PMID: 38490069
