GO:1901875 positive regulation of post-translational protein modification: Regulatory Signaling, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1901875 describes any process that activates or increases the frequency, rate or extent of post-translational protein modification (PTM), a central layer of cellular regulation.
• Positive regulation of PTM controls immune checkpoint abundance, metabolic enzyme activity, chromatin state and protein stability, as shown for PD-L1, GAPDH, p53, GLUT1 and histones [1,3,4,5,6].
• Writers, erasers and readers of PTMs are the core effectors whose upstream activation defines this GO term, including lactyltransferases, serotonyltransferases, palmitoyltransferases, UFM1-conjugating machinery and O-GlcNAc transferase [2,3,4,5,8].
• Dysregulated PTM upregulation drives tumor immune evasion, metabolic reprogramming, cardiac inflammation and endometrial malignancy [1,2,5,6,7,8].
• CRISPR knockout, point-mutation, knock-in and overexpression models are the standard tools to test causality of positive PTM regulators [1,4,5,8].
• EDITGENE provides end-to-end CRISPR cell model and library screening services to dissect GO:1901875-related mechanisms.
Description
Post-translational protein modification (PTM) is the enzymatic addition or removal of chemical groups on proteins after translation, and its positive regulation is captured by the Gene Ontology term GO:1901875, defined as any process that activates or increases the frequency, rate or extent of post-translational protein modification. This term sits at the top of a regulatory hierarchy that controls when and where writers, erasers and readers of PTMs act, thereby shaping protein stability, localization, activity and interaction networks [1,4]. Because PTMs are reversible and context-dependent, their positive regulation is a major node for signal integration in immunity, metabolism and cancer [3,6].
positive regulation of post-translational protein modification At A Glance
| GO ID | GO:1901875 |
|---|---|
| GO term | positive regulation of post-translational protein modification |
| Ontology | biological_process |
| Synonym | activation of PTM; positive regulation of PTM; upregulation of post-translational modification |
| Major function | Increases the frequency, rate or extent of post-translational protein modification |
| Example effectors | PD-L1, GAPDH, p53, GLUT1, histones, OGT |
| Related processes | Lactylation, serotonylation, UFMylation, S-palmitoylation, O-GlcNAcylation, ubiquitination |
| Disease relevance | Cancer immune evasion, metabolic disease, cardiac inflammation, endometrial malignancy |
What Is GO:1901875?
GO:1901875 is a biological_process term meaning any molecular event or pathway that activates or increases the frequency, rate or extent of post-translational protein modification. It does not describe the modification reaction itself, but the upstream positive control of that reaction, including activation of enzymes that add or remove PTMs, recruitment of substrates, and relief of inhibitory constraints [1,4,8].
Why Is positive regulation of post-translational protein modification Important in Cell Biology?
Positive regulation of PTM is important because it determines the abundance and activity of key signaling proteins without changing transcript levels, enabling rapid and reversible cellular responses. For example, increased PD-L1 modification and stabilization alters antitumor immunity, while enhanced GAPDH serotonylation supports CD8+ T cell glycolytic metabolism and antitumor function. Similarly, positive regulation of p53 UFMylation maintains tumor suppressor stability, and upregulation of GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis. These examples show that GO:1901875 is a central control point in health and disease.
• Controls immune checkpoint protein stability and tumor immune evasion through PD-L1 regulation.
• Links metabolic state to immune cell function via GAPDH serotonylation.
• Maintains tumor suppressor p53 stability through UFMylation.
• Promotes cancer metabolism by enhancing GLUT1 S-palmitoylation in glioblastoma.
• Drives CD8+ T cell metabolism and function through histone lactylation.
• Contributes to liver cancer growth via PD-L1 delactylation and nuclear translocation.
• Restrains endometrial malignancy through FBXO31-mediated ubiquitination of OGT and O-GlcNAcylation homeostasis.
• Triggers neutrophil trafficking and cardiac inflammation via S100a9 lactylation.
• Provides reversible, rapid control of protein function without transcriptional changes [1,4].
• Offers therapeutic targets for cancer, inflammation and metabolic disorders [2,5,7].
What Happens During positive regulation of post-translational protein modification?
Activation of PTM writer enzymes
In simple terms: The enzymes that add chemical marks to proteins are switched on.
Positive regulation of PTM often begins with activation of writer enzymes such as lactyltransferases, serotonyltransferases, palmitoyltransferases and UFM1-conjugating enzymes. For instance, DHHC9-mediated S-palmitoylation of GLUT1 is increased in glioblastoma, promoting glycolysis and tumorigenesis. Similarly, GAPDH serotonylation is enhanced to couple glycolytic metabolism to antitumor immunity.
Recruitment and availability of substrates
In simple terms: The target proteins must be present and accessible for modification.
Upregulation of PTM requires substrate recruitment. PD-L1 is a key substrate whose modification and stabilization are positively regulated in the tumor microenvironment. Histone lactylation depends on available lactate and histone substrates, and its increase drives CD8+ T cell metabolism and function.
Removal of inhibitory constraints
In simple terms: Brakes on the modification machinery are released.
Positive regulation can occur by relieving inhibition. For example, UFMylation maintains p53 stability by antagonizing its ubiquitination, effectively increasing the net positive modification state of p53. FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis, showing that regulated degradation of a PTM enzyme can also shape the overall modification landscape.
Signal integration and feedback
In simple terms: Multiple signals converge to tune the level of modification.
Positive regulation integrates metabolic and immune signals. S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation, illustrating how a specific PTM upregulation translates into a physiological response. PD-L1 delactylation promotes nuclear translocation and liver cancer growth, showing that the balance of modification and removal is critical.
Key Genes Involved in GO:1901875 positive regulation of post-translational protein modification
The following genes and proteins are experimentally validated effectors or substrates whose positive regulation of PTM has been documented in the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PD-L1 (CD274) | Immune checkpoint protein whose modification is positively regulated | Tumor immune evasion and immunotherapy target [1,7] |
| GAPDH | Glycolytic enzyme regulated by serotonylation | CD8+ T cell metabolism and antitumor immunity |
| TP53 | Tumor suppressor stabilized by UFMylation | Cancer biology and protein stability |
| GLUT1 (SLC2A1) | Glucose transporter regulated by S-palmitoylation | Glioblastoma glycolysis and tumorigenesis |
| Histones | Chromatin proteins modified by lactylation | CD8+ T cell metabolism and function |
| OGT | O-GlcNAc transferase regulated by ubiquitination | Endometrial malignancy and O-GlcNAcylation homeostasis |
| S100A9 | Calcium-binding protein regulated by lactylation | Neutrophil trafficking and cardiac inflammation |
| DHHC9 (ZDHHC9) | Palmitoyltransferase for GLUT1 | Glioblastoma metabolism |
| FBXO31 | E3 ubiquitin ligase targeting OGT | Endometrial cancer restraint |
| UFM1 | Ubiquitin-like modifier for p53 | p53 stability and tumor suppression |
| SQLE | Squalene epoxidase regulated by PD-L1 nuclear function | Liver cancer growth |
| Lactyltransferases | Enzymes adding lactyl groups | Histone and non-histone lactylation [2,6] |
| Serotonyltransferases | Enzymes adding serotonin groups | GAPDH serotonylation |
| Delactylases | Enzymes removing lactyl groups | PD-L1 delactylation and nuclear translocation |
| Ubiquitin ligases | Enzymes adding ubiquitin | p53 and OGT regulation [4,8] |
| Deubiquitinases | Enzymes removing ubiquitin | Counterbalance of ubiquitination |
| O-GlcNAcase (OGA) | Enzyme removing O-GlcNAc | O-GlcNAcylation homeostasis |
How Is positive regulation of post-translational protein modification Regulated?
Positive regulation of PTM is itself regulated by upstream signals including metabolic flux, immune receptor activation and stress pathways. For example, lactate availability drives histone lactylation and CD8+ T cell function, while inflammatory signals promote S100a9 lactylation and neutrophil trafficking. The balance between writers and erasers, such as lactyltransferases and delactylases, determines the net modification state of substrates like PD-L1. Additionally, E3 ligases and deubiquitinases control the stability of PTM enzymes, as shown for FBXO31-mediated ubiquitination of OGT.
positive regulation of post-translational protein modification and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PD-L1 (CD274) | Cancer immune evasion, liver cancer | Knockout and point-mutation cell lines [1,7] |
| GAPDH | CD8+ T cell metabolism, antitumor immunity | Overexpression and point-mutation models |
| TP53 | Tumor suppression, protein stability | Knock-in and knockout models |
| GLUT1 (SLC2A1) | Glioblastoma glycolysis | Knockout and overexpression models |
| OGT | Endometrial malignancy | Knockout and tagged knock-in models |
Cancer immune evasion and immunotherapy
Positive regulation of PTM directly impacts immune checkpoint biology. PD-L1 modification and stabilization in the tumor microenvironment promote immune evasion, and targeting these pathways is a major therapeutic strategy. PD-L1 delactylation and nuclear translocation accelerate liver cancer growth by elevating SQLE transcription activity, linking PTM regulation to lipid metabolism and tumor progression.
Metabolic reprogramming in cancer
Upregulated PTMs support cancer metabolism. DHHC9-mediated GLUT1 S-palmitoylation enhances glycolysis and tumorigenesis in glioblastoma. GAPDH serotonylation couples glycolytic metabolism to antitumor immunity, showing that metabolic PTMs can also support immune function.
Cardiac inflammation and neutrophil trafficking
S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation in myocardial ischemia/reperfusion injury, demonstrating that positive regulation of PTM contributes to inflammatory cardiovascular disease.
Endometrial malignancy and O-GlcNAcylation
FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy, highlighting the tumor-suppressive role of regulated PTM enzyme turnover.
From positive regulation of post-translational protein modification-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a PTM writer affect substrate modification? | CRISPR knockout cell line [1,5] |
| Does a specific amino acid in the substrate control modification? | Point-mutation knock-in [3,4] |
| Does tagging a PTM enzyme alter its localization? | Tagged knock-in |
| Does overexpression of a PTM regulator drive transformation? | Overexpression cell model [5,7] |
| Which genes regulate a PTM pathway globally? | CRISPR library screening [1,8] |
| Can a PTM inhibitor reverse a disease phenotype? | Pharmacological perturbation with CRISPR validation [2,6] |
How to Study the positive regulation of post-translational protein modification Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Mass spectrometry | PTM identity and site occupancy | Global PTM profiling [1,3,6] |
| CRISPR knockout screening | Genes required for PTM upregulation | Discovery of regulators [1,8] |
| Western blot with PTM antibodies | Steady-state PTM levels | Validation of specific modifications [4,5] |
| Co-immunoprecipitation | Protein-protein interactions | Writer-substrate binding [4,8] |
| Immunofluorescence | Subcellular localization of PTMs | Nuclear translocation studies |
| Proximity labeling | Enzyme-substrate proximity | Mapping PTM machinery |
| RNA-seq | Transcriptional consequences | Downstream effects of PTM changes [1,6] |
| Metabolic assays | Glycolysis and metabolic flux | Functional impact of PTMs [3,5] |
Proteomics and PTM-specific enrichment
Mass spectrometry-based proteomics with PTM-specific enrichment (e.g., lactyl, serotonyl, palmitoyl, UFM1) identifies modified substrates and quantifies changes upon positive regulation. This approach has been used to map PD-L1, GAPDH and histone modifications [1,3,6].
CRISPR screening and functional genomics
Genome-wide CRISPR knockout or activation screens can identify positive regulators of a given PTM by coupling modification readouts to survival or reporter assays. Such screens are powerful for discovering new writers, erasers and regulatory factors [1,8].
Imaging and proximity labeling
Fluorescence microscopy and proximity labeling (e.g., BioID, APEX) can visualize where PTMs occur and which enzymes are in proximity. These methods have clarified nuclear translocation of PD-L1 and subcellular localization of OGT [7,8].
Biochemical assays and co-immunoprecipitation
In vitro modification assays, co-immunoprecipitation and western blotting with PTM-specific antibodies validate direct regulation. For example, UFMylation of p53 and its antagonism of ubiquitination were demonstrated biochemically.
How CRISPR Can Be Used to Study GO:1901875 positive regulation of post-translational protein modification
Knockout
CRISPR knockout of a putative PTM writer or regulator can abolish the modification and reveal its function. For example, knockout of DHHC9 reduces GLUT1 palmitoylation and glioblastoma glycolysis, and knockout of FBXO31 alters OGT stability and O-GlcNAcylation.
Point Mutation
Point mutations at specific modification sites or catalytic residues can dissect causality. For instance, mutating the serotonylation site on GAPDH or the UFMylation site on p53 can test whether the modification is required for the observed phenotype [3,4].
Knock-in
Knock-in of tagged or mutant alleles allows tracking of PTM enzymes and substrates in their native context. Tagged knock-in of OGT or PD-L1 can reveal dynamic localization and modification states [7,8].
Overexpression
Overexpression of a PTM regulator can drive pathway activation and disease phenotypes. Overexpression of GLUT1 or PD-L1 mutants has been used to study metabolic and immune effects [1,5].
How EDITGENE Supports positive regulation of post-translational protein modification Research
Researchers studying positive regulation of post-translational protein modification-related genes often need to determine whether a candidate gene is causally involved in a specific PTM pathway, and CRISPR-based cell models provide the most direct way to test this.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of post-translational protein modification research.
Frequently Asked Questions About positive regulation of post-translational protein modification
What is GO:1901875?
GO:1901875 is the Gene Ontology term for positive regulation of post-translational protein modification, meaning any process that activates or increases the frequency, rate or extent of PTM.
What genes are involved in positive regulation of post-translational protein modification?
Key genes include PD-L1, GAPDH, TP53, GLUT1, OGT, S100A9, DHHC9 and FBXO31, as shown in cancer, immune and metabolic studies [1,2,3,4,5,8].
How does positive regulation of PTM affect cancer?
It can stabilize immune checkpoint proteins like PD-L1, enhance glycolysis via GLUT1 palmitoylation, and promote tumor growth through PD-L1 delactylation and nuclear translocation [1,5,7].
What is the role of lactylation in this process?
Lactylation is a PTM positively regulated by metabolic signals; histone lactylation drives CD8+ T cell function, and S100a9 lactylation triggers cardiac inflammation [2,6].
How can CRISPR be used to study GO:1901875?
CRISPR knockout, point mutation, knock-in and overexpression models allow causal testing of PTM regulators and substrates [1,3,4,5,8].
What diseases are linked to dysregulated PTM upregulation?
Cancer immune evasion, glioblastoma, liver cancer, endometrial malignancy and cardiac inflammation are linked to altered PTM regulation [1,2,5,7,8].
What methods are used to measure positive regulation of PTM?
Mass spectrometry, PTM-specific western blotting, co-immunoprecipitation, imaging and CRISPR screens are commonly used [1,3,4,6,8].
Is UFMylation a type of post-translational modification?
Yes, UFMylation is a ubiquitin-like modification; its positive regulation maintains p53 stability by antagonizing ubiquitination.
What is the difference between PTM and positive regulation of PTM?
PTM is the modification itself, while positive regulation of PTM (GO:1901875) describes the upstream processes that increase its frequency, rate or extent.
Can EDITGENE help with CRISPR models for PTM research?
Yes, EDITGENE provides knockout, point-mutation, knock-in, overexpression and library screening services for PTM-related genes [1,5,8].
Conclusion
GO:1901875 captures the positive regulation of post-translational protein modification, a process that controls protein function, stability and localization across immunity, metabolism and cancer. The cited literature demonstrates that dysregulated PTM upregulation contributes to tumor immune evasion, metabolic reprogramming, cardiac inflammation and endometrial malignancy [1,2,5,6,7,8]. Understanding these mechanisms requires precise genetic models, and CRISPR-based approaches are essential for causal dissection.
References
- 1. Yi M et al.. 2021. Regulation of PD-L1 expression in the tumor microenvironment.. J Hematol Oncol 14(1):10 PMID: 33413496
- 2. Wang X et al.. 2025. S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation in myocardial ischemia/reperfusion injury.. J Clin Invest 135(24) PMID: 41066195
- 3. Wang X et al.. 2024. A GAPDH serotonylation system couples CD8(+) T cell glycolytic metabolism to antitumor immunity.. Mol Cell 84(4):760-775.e7 PMID: 38215751
- 4. Liu J et al.. 2020. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.. Nat Cell Biol 22(9):1056-1063 PMID: 32807901
- 5. Zhang Z et al.. 2021. DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis.. Nat Commun 12(1):5872 PMID: 34620861
- 6. Raychaudhuri D et al.. 2024. Histone lactylation drives CD8(+) T cell metabolism and function.. Nat Immunol 25(11):2140-2151 PMID: 39375549
- 7. Wang X et al.. 2025. PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity.. Cancer Lett 630:217901 PMID: 40614853
- 8. Zhang N et al.. 2025. FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy.. Nat Commun 16(1):1274 PMID: 39894887
