GO:0002683 negative regulation of immune system process: Immune Checkpoint Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0002683 describes any biological process that stops, prevents, or reduces the frequency, rate, or extent of an immune system process [1,3].
• Negative regulation is essential to prevent autoimmunity and immunopathology while allowing effective host defense [3,4].
• Key molecular brakes include palmitoylation by ZDHHC18, deacetylation by SIRT2, and inhibition of MAVS aggregation by WDR77 [1,2,5].
• Tripartite motif (TRIM) proteins and NLRX1 are established negative regulators of immune signaling [6,8].
• CD1-restricted T cell responses are themselves subject to negative regulation by dedicated molecular players.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal dissection of negative regulators in immune cells.
Description
The Gene Ontology term GO:0002683, negative regulation of immune system process, captures any process that stops, prevents, or reduces the frequency, rate, or extent of an immune system process [1,3]. Immune responses must be tightly controlled because unchecked activation can damage host tissues, whereas insufficient restraint can permit autoimmunity or chronic inflammation [3,4]. This term therefore encompasses a broad set of molecular brakes that act on innate and adaptive immunity, including palmitoylation-dependent inhibition of cGAS, deacetylation of G3BP1 to dampen STING signaling, and prevention of prion-like MAVS aggregation [1,2,5]. Understanding these negative regulators is critical for therapeutic modulation of immunity in infection, cancer, and autoinflammatory disease [6,8].
negative regulation of immune system process At A Glance
| GO ID | GO:0002683 |
|---|---|
| GO term | negative regulation of immune system process |
| Ontology | biological_process |
| Synonym | down regulation of immune system process; down-regulation of immune system process; downregulation of immune system process; inhibition of immune system process |
| Major function | Stops, prevents, or reduces the frequency, rate, or extent of an immune system process |
| Biological context | Innate and adaptive immunity, including cGAS-STING, MAVS, and lymphocyte coreceptor signaling |
| Representative regulators | ZDHHC18, SIRT2, WDR77, TRIM proteins, NLRX1, CD1-related negative regulators |
| Disease relevance | Autoimmunity, chronic inflammation, cancer immune evasion, and antiviral restriction |
What Is GO:0002683?
In plain terms, GO:0002683 refers to any biological process that stops, prevents, or reduces the frequency, rate, or extent of an immune system process [1,3]. It is a biological_process ontology term that includes molecular events such as post-translational modification of immune sensors, sequestration or degradation of signaling adaptors, and inhibitory receptor engagement that collectively restrain immune activation [1,2,4,5].
Why Is negative regulation of immune system process Important in Cell Biology?
Negative regulation of immune system processes is essential for maintaining immune homeostasis and preventing collateral tissue damage during infection [3,4]. Dysregulation of these brakes can lead to autoimmunity, chronic inflammatory disease, or impaired pathogen clearance, making them attractive targets for therapeutic intervention [6,8].
• Prevents autoimmunity by restraining self-reactive lymphocyte activation.
• Limits immunopathology during antiviral responses by dampening cGAS-STING and MAVS signaling [1,2,5].
• Controls the duration and intensity of innate immune signaling through post-translational modifications [1,2].
• TRIM proteins provide a paradigm for positive and negative regulation of immune signaling.
• NLRX1 exemplifies multifaceted negative regulation of immune system function.
• CD1-restricted responses are subject to dedicated negative regulators.
• Dysregulation contributes to inflammatory and autoimmune diseases [3,4].
• Therapeutic targeting of negative regulators can boost antitumor immunity [6,8].
• Understanding these processes informs vaccine adjuvant design.
• CRISPR models enable causal testing of candidate negative regulators in immune cells [1,2,5].
What Happens During negative regulation of immune system process?
Post-translational modification of immune sensors
In simple terms: Chemical tags are added to immune proteins to switch them off.
ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation, directly modifying the sensor to reduce its activity. Similarly, SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1, thereby dampening downstream signaling. These modifications provide reversible brakes on innate immune activation.
Inhibition of signaling adaptor aggregation
In simple terms: Helper proteins are stopped from clumping together, which blocks the immune alarm.
WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response, preventing the formation of signaling platforms that would otherwise amplify interferon production. This illustrates how negative regulation can act at the level of higher-order protein assembly.
Regulation by TRIM and NLRX1 families
In simple terms: Dedicated families of proteins act as brakes on immune signaling.
Tripartite motif (TRIM) proteins provide both positive and negative regulation of immune signaling, with several members acting as E3 ligases that target immune adaptors for degradation or sequestration. NLRX1 is a multifaceted and enigmatic regulator that can inhibit immune system function through interactions with mitochondrial and cytosolic signaling complexes.
Inhibitory coreceptor and CD1 pathways
In simple terms: Special receptors on immune cells deliver stop signals.
Lymphocyte coreceptors include inhibitory receptors that negatively regulate T cell activation, helping to set thresholds for immune responses. CD1 displays its own negative regulators, indicating that even non-classical antigen-presenting pathways are subject to dedicated inhibitory control.
Integration with Drosophila and evolutionary models
In simple terms: Even insects have built-in brakes on immunity, showing this is an ancient principle.
Studies in Drosophila reveal positive and negative regulation of the immune response, demonstrating that negative control of immunity is evolutionarily conserved and can be dissected genetically. This provides a framework for identifying core negative regulators that operate across species.
Key Genes Involved in GO:0002683 negative regulation of immune system process
The following genes and proteins are experimentally validated participants in negative regulation of immune system processes.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ZDHHC18 | Palmitoyltransferase that negatively regulates cGAS-mediated innate immunity | Target for modulating cGAS-dependent antiviral and autoimmune responses |
| SIRT2 | Deacetylase that negatively regulates cGAS-STING by deacetylating G3BP1 | Metabolic and epigenetic brake on innate immunity |
| WDR77 | Inhibits prion-like aggregation of MAVS to limit antiviral innate immune response | Regulator of mitochondrial antiviral signaling |
| TRIM proteins | Family of E3 ligases with positive and negative roles in immune signaling | Broad modulators of innate and adaptive immunity |
| NLRX1 | Multifaceted negative regulator of immune system function | Mitochondria-associated inhibitor of immune signaling |
| CD1 | Antigen-presenting molecule with its own negative regulators | Lipid antigen presentation and T cell regulation |
| Lymphocyte coreceptors | Inhibitory receptors that dampen T cell activation | Checkpoint control in adaptive immunity |
| Drosophila immune regulators | Conserved positive and negative regulators of insect immunity | Genetic model for innate immune braking |
| G3BP1 | Substrate of SIRT2 in cGAS-STING negative regulation | Stress granule protein linking deacetylation to immune suppression |
| MAVS | Adaptor whose aggregation is inhibited by WDR77 | Mitochondrial antiviral signaling node |
| cGAS | DNA sensor whose activity is reduced by ZDHHC18 palmitoylation | Cytosolic DNA sensing and autoimmunity |
| STING | Signaling adaptor negatively regulated via SIRT2-G3BP1 axis | Interferonopathies and cancer immunity |
| TRIM E3 ligases | Enzymes that ubiquitinate immune signaling components | Drug targets for immune modulation |
| NLRX1 interacting partners | Mitochondrial and cytosolic signaling complexes | Context-dependent immune regulation |
| Inhibitory coreceptors | Receptors delivering negative signals in lymphocytes | Checkpoint blockade targets |
| CD1-restricted T cells | Lipid-reactive T cells subject to negative regulation | Autoimmunity and infection models |
| Drosophila NF-kB regulators | Negative regulators of insect immune signaling | Evolutionary conservation studies |
How Is negative regulation of immune system process Regulated?
Negative regulation of immune system processes is itself regulated at multiple levels. Post-translational modifications such as palmitoylation and deacetylation provide reversible control of immune sensor activity [1,2]. Protein aggregation and phase separation of adaptors like MAVS are directly inhibited by dedicated factors such as WDR77. TRIM proteins and NLRX1 integrate ubiquitin-dependent and mitochondrial signals to fine-tune immune output [6,8]. Inhibitory coreceptors and CD1-associated negative regulators set thresholds for lymphocyte activation [4,7].
negative regulation of immune system process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ZDHHC18 | cGAS-mediated autoimmunity and antiviral restriction | Knockout and point-mutation in myeloid cells |
| SIRT2 | cGAS-STING-driven interferonopathy and inflammation | Deacetylase-dead knock-in and knockout models |
| WDR77 | MAVS aggregation-related antiviral and autoimmune phenotypes | Aggregation reporter knock-in and knockout |
| TRIM proteins | Cancer immune evasion and autoimmunity | E3 ligase-dead point mutants and knockouts |
| NLRX1 | Inflammatory and metabolic immune dysregulation | Knockout and overexpression in macrophages |
Autoimmunity and autoinflammation
Loss of negative regulation can lead to inappropriate immune activation against self, contributing to autoimmune and autoinflammatory conditions [3,4]. For example, impaired braking of cGAS-STING signaling is associated with interferonopathies and chronic inflammation [1,2].
Cancer immune evasion
Tumors can exploit negative regulators of immune system processes to evade immune detection [6,8]. Targeting these brakes, such as TRIM proteins or NLRX1, may enhance antitumor immunity [6,8].
Antiviral restriction and immunopathology
Negative regulation of MAVS aggregation and cGAS activity limits antiviral innate immune responses, which can prevent immunopathology but may also permit viral persistence [1,2,5].
Lipid antigen presentation disorders
CD1-restricted T cell responses and their negative regulators are implicated in lipid-antigen-driven immune disorders.
From negative regulation of immune system process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene a negative regulator of cGAS signaling? | CRISPR knockout in THP-1 or primary macrophages |
| Does a specific post-translational modification site control immune braking? | Point-mutation knock-in of the modified residue [1,2] |
| Does a negative regulator inhibit MAVS aggregation? | Tagged knock-in with aggregation reporter |
| Can overexpression of a negative regulator suppress autoimmunity? | Overexpression cell models and in vivo delivery |
| Which TRIM family members dampen immune signaling? | CRISPR library screening in immune reporter cells |
| Is NLRX1 function context-dependent? | Conditional knockout and rescue with point mutants |
How to Study the negative regulation of immune system process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Loss-of-function effects on immune signaling | Identify negative regulators of cGAS-STING [1,2] |
| Point-mutation knock-in | Specific residue contribution to immune braking | Test palmitoylation or acetylation sites [1,2] |
| Proteomics | Post-translational modifications and interactors | Map ZDHHC18 or SIRT2 substrates [1,2] |
| SDD-AGE | Prion-like aggregation of MAVS | Assess WDR77 inhibition of aggregation |
| ISRE reporter assay | Interferon pathway activity | Quantify negative regulation in immune cells [1,2] |
| Co-immunoprecipitation | Protein-protein interactions | Study TRIM and NLRX1 complexes [6,8] |
| Flow cytometry | Immune cell activation markers | Measure inhibitory coreceptor effects |
| RNA-seq | Transcriptional changes in immune pathways | Profile negative regulator knockouts [3,6] |
CRISPR knockout and point-mutation screens
Pooled CRISPR knockout and point-mutation screens can identify genes that negatively regulate immune system processes, such as those controlling cGAS-STING or MAVS signaling [1,2,5].
Post-translational modification profiling
Mass spectrometry-based proteomics and acyl-biotin exchange assays can map palmitoylation and acetylation events on immune regulators like cGAS and G3BP1 [1,2].
Aggregation and imaging assays
Fluorescence microscopy and semi-denaturing detergent agarose gel electrophoresis (SDD-AGE) can monitor prion-like aggregation of MAVS and its inhibition by WDR77.
Immune signaling reporter systems
Luciferase or fluorescent reporters driven by interferon-stimulated response elements (ISRE) enable quantitative measurement of negative regulation in live cells [1,2,6].
How CRISPR Can Be Used to Study GO:0002683 negative regulation of immune system process
Knockout
CRISPR knockout of candidate negative regulators such as ZDHHC18 or SIRT2 can reveal their role in dampening cGAS-STING signaling, often resulting in enhanced interferon responses [1,2].
Point Mutation
Point-mutation knock-in of specific modification sites, such as the palmitoylation site on cGAS or acetylation site on G3BP1, allows precise testing of whether a single residue mediates negative regulation [1,2].
Knock-in
Tagged knock-in of MAVS or other adaptors enables real-time monitoring of aggregation and its inhibition by factors like WDR77.
Overexpression
Overexpression of negative regulators such as NLRX1 or TRIM proteins can suppress immune activation and is useful for testing therapeutic potential in autoimmunity models [6,8].
How EDITGENE Supports negative regulation of immune system process Research
Researchers studying negative regulation of immune system process-related genes often need to determine whether a candidate gene is causally involved in restraining immune activation, and CRISPR-based models provide the most direct way to test this.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of immune system process research.
Frequently Asked Questions About negative regulation of immune system process
What is negative regulation of immune system process?
It is any biological process that stops, prevents, or reduces the frequency, rate, or extent of an immune system process, as defined by GO:0002683 [1,3].
What genes are involved in negative regulation of immune system process?
Genes include ZDHHC18, SIRT2, WDR77, TRIM family members, NLRX1, and CD1-related negative regulators [1,2,5,6,7,8].
How does ZDHHC18 negatively regulate cGAS-mediated innate immunity?
ZDHHC18 palmitoylates cGAS, reducing its activity and dampening innate immune signaling.
What is the role of SIRT2 in the cGAS-STING pathway?
SIRT2 deacetylates G3BP1 to negatively regulate the cGAS-STING pathway.
How does WDR77 limit antiviral innate immune response?
WDR77 inhibits prion-like aggregation of MAVS, thereby limiting antiviral innate immune signaling.
What are TRIM proteins in immune regulation?
TRIM proteins are a family of E3 ligases that provide both positive and negative regulation of immune signaling.
What is NLRX1 and how does it regulate immunity?
NLRX1 is a multifaceted and enigmatic regulator of immune system function, often acting as a negative regulator.
How are CD1-restricted T cell responses negatively regulated?
CD1 displays its own negative regulators that dampen lipid-antigen-driven T cell responses.
Why is negative regulation of immune system process important for disease?
It prevents autoimmunity and immunopathology, and its dysregulation contributes to inflammatory and autoimmune diseases [3,4].
What CRISPR models are used to study negative regulation of immune system process?
Knockout, point-mutation knock-in, tagged knock-in, and overexpression models in immune cells are commonly used [1,2,5,6,8].
Conclusion
GO:0002683, negative regulation of immune system process, encompasses essential molecular brakes that prevent excessive immune activation. Key regulators such as ZDHHC18, SIRT2, WDR77, TRIM proteins, and NLRX1 illustrate diverse mechanisms including post-translational modification and inhibition of adaptor aggregation [1,2,5,6,8]. Understanding these processes is critical for developing therapies for autoimmunity, inflammation, and cancer.
References
- 1. Shi C et al.. 2022. ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation.. EMBO J 41(11):e109272 PMID: 35438208
- 2. Li Y et al.. 2023. SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1.. EMBO Rep 24(12):e57500 PMID: 37870259
- 3. Aggarwal K et al.. 2008. Positive and negative regulation of the Drosophila immune response.. BMB Rep 41(4):267-77 PMID: 18452646
- 4. Olive D. 2006. [Lymphocyte coreceptors].. Med Sci (Paris) 22(12):1069-74 PMID: 17156728
- 5. Li J et al.. 2023. WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response.. Nat Commun 14(1):4824 PMID: 37563140
- 6. Versteeg GA et al.. 2014. InTRIMsic immunity: Positive and negative regulation of immune signaling by tripartite motif proteins.. Cytokine Growth Factor Rev 25(5):563-76 PMID: 25172371
- 7. Shahine A et al.. 2023. CD1 displays its own negative regulators.. Curr Opin Immunol 83:102339 PMID: 37245411
- 8. Nagai-Singer MA et al.. 2019. NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function.. Front Immunol 10:2419 PMID: 31681307
