# RIGI Gene: Structure, Function, and Clinical Significance
## Key Takeaways
- RIGI (DDX58) is a cytosolic pattern recognition receptor that acts as the primary sensor for viral RNA, initiating type I interferon and pro-inflammatory cytokine responses critical for antiviral immunity.
- Its structure comprises N-terminal CARDs for MAVS interaction, a central helicase domain for RNA binding and ATP hydrolysis, and a C-terminal domain that recognizes the 5'-triphosphate moiety of viral RNA, enabling self/non-self discrimination.
- Germline loss-of-function mutations in *RIGI* lead to primary immunodeficiency with increased susceptibility to viral infections, while dysregulated expression is implicated in autoimmune diseases like SLE and RA due to excessive type I interferon production.
- Viruses have evolved diverse strategies to antagonize RIGI signaling, including direct binding, inhibition of ATPase activity, and interference with ubiquitination or downstream adaptor proteins like MAVS.
- RIGI agonists, particularly synthetic RNA molecules, are being developed as immunotherapeutic agents for cancer, aiming to overcome tumor immunosuppression and enhance anti-tumor immunity, and as vaccine adjuvants to boost adaptive responses.
- Somatic alterations, such as promoter hypermethylation leading to RIGI silencing, are observed in cancers, where restoring RIGI expression can promote apoptosis and immune surveillance.
---
## Executive Summary & Key Metadata
The **RIGI** gene (Retinoic Acid-Inducible Gene I), also known as **DDX58** (DEAD-box helicase 58), encodes a cytosolic pattern recognition receptor (PRR) that serves as the primary sensor for non-self RNA species introduced during viral infection. As the founding member of the RIG-I-like receptor (RLR) family, RIGI orchestrates the initiation of type I interferon (IFN) and pro-inflammatory cytokine responses, establishing a critical first line of defense against RNA viruses, certain DNA viruses, and intracellular bacteria [1, 2, 3]. Beyond its canonical role in antiviral immunity, RIGI is increasingly recognized as a nexus for tumor immune surveillance, inflammatory disease pathology, and a promising target for immunotherapeutic intervention [4, 5, 6].
| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | RIGI (DDX58) |
| **UniProt Accession** | O95786 |
| **Representative PDB ID** | True (e.g., 4AYA, 2ZA5, 3OG8) |
| **Chromosomal Locus** | 9p21.1 (GRCh38: chr9:32,455,302-32,526,318) |
| **Primary Molecular Function** | Cytosolic double-stranded RNA (dsRNA) and 5'-triphosphate (5'ppp) RNA sensor; ATP-dependent helicase; signal transducer activating MAVS-dependent innate immune signaling |
| **Disease & Pathology Associations** | Viral susceptibility (influenza, RSV, HIV, HSV-1), autoimmune diseases (SLE, RA), glioblastoma, pancreatic cancer, breast cancer, radiation-induced genomic instability |
## 1. Genomic Locus, Chromosomal Organization & Isoforms
### 1.1 Chromosomal Location and Gene Structure
The human *RIGI* gene is located on the short (p) arm of chromosome 9 at cytogenetic band **9p21.1**. This locus is gene-dense and frequently altered in human cancers, with deletions in this region associated with tumor progression. The gene spans approximately 71 kilobases (kb) of genomic DNA, oriented on the minus (Crick) strand. The mature mRNA transcript is approximately 3.9 kb and encodes a protein of 925 amino acids with a predicted molecular weight of ~106 kDa.
The genomic architecture of *RIGI* comprises **18 exons** and **17 introns**, with the translation start codon (ATG) located in exon 1 and the stop codon in exon 18. The exon-intron boundaries largely correspond to functional protein domains, a feature common to multi-domain signaling proteins. Exons 2 and 3 encode the tandem N-terminal caspase activation and recruitment domains (CARDs), exons 4-9 encode the core helicase ATPase domain, and exons 10-18 encode the C-terminal regulatory domain (CTD) and repressor domain (RD) [1, 7].
### 1.2 Promoter Architecture and Transcriptional Regulation
The *RIGI* promoter region lacks a canonical TATA box but contains multiple CpG islands, making its expression subject to epigenetic regulation via DNA methylation. The proximal promoter contains binding sites for several key transcription factors, including:
- **Interferon Regulatory Factors (IRFs):** IRF1 and IRF3 binding sites are critical for IFN-dependent and IFN-independent induction of *RIGI* transcription, respectively. This creates a positive feedback loop where initial RIGI signaling leads to IRF3 activation, which in turn upregulates *RIGI* expression to amplify the antiviral state.
- **Signal Transducers and Activators of Transcription (STATs):** STAT1 and STAT2, activated downstream of type I IFN receptor (IFNAR) signaling, bind to interferon-stimulated response elements (ISREs) and gamma-activated sequences (GAS) within the promoter.
- **Nuclear Factor-κB (NF-κB):** Binding sites for NF-κB (p65/p50 heterodimer) are present, linking pro-inflammatory cytokine signaling to *RIGI* expression.
- **Retinoic Acid Receptors (RARs):** The gene name derives from its induction by retinoic acid, which acts via RAR/RXR heterodimers binding to retinoic acid response elements (RAREs) in the promoter.
### 1.3 Alternative Splicing and Isoforms
Alternative splicing of the *RIGI* pre-mRNA generates multiple transcript variants. The primary canonical isoform (ENST00000378645.8) encodes the full-length 925-amino acid protein. A well-characterized splice variant lacks exon 8, resulting in a frameshift and premature stop codon. This isoform, often termed RIG-I-S or dominant-negative RIGI, encodes a truncated protein that retains the CARDs but lacks the helicase and CTD domains. This truncated isoform acts as a dominant-negative inhibitor of full-length RIGI signaling by competing for MAVS binding, providing a mechanism for fine-tuning the amplitude of the innate immune response [8]. The expression ratio of these isoforms is cell-type specific and can be modulated by viral infection, representing a post-transcriptional regulatory layer.
## 2. 3D Protein Domain Architecture & Structural Biology
The RIGI protein is a modular, multi-domain RNA helicase. Its architecture is exquisitely designed for the sequential processes of RNA ligand recognition, ATP hydrolysis, and signal transduction. High-resolution crystal structures have been solved for the individual domains and, more recently, for the full-length protein in various conformational states, revealing a dynamic "signal-on" and "signal-off" mechanism [9].
### 2.1 N-Terminal Tandem CARDs (aa 1-200)
The N-terminus contains two tandem CARDs (CARD1: aa 1-90; CARD2: aa 95-200). In the unliganded, "closed" conformation of RIGI, these CARDs are sequestered by intramolecular interactions with the helicase domain and the CTD, preventing spontaneous signaling. Upon RNA binding and ATP hydrolysis, a dramatic conformational change releases the CARDs, allowing them to undergo **K63-linked polyubiquitination**. This ubiquitination, mediated by E3 ligases such as TRIM25 and MEX3C [10], is a prerequisite for CARD-CARD interaction with the adaptor protein MAVS (Mitochondrial Antiviral Signaling protein, also known as VISA, IPS-1, or Cardif). The CARDs form a tetrameric complex with the N-terminal CARD of MAVS, nucleating the formation of prion-like MAVS aggregates on the mitochondrial membrane [11, 12].
### 2.2 Central Helicase Domain (aa 225-790)
The central region is a Superfamily 2 (SF2) helicase, comprising two RecA-like domains (Hel1 and Hel2) and an insertion domain (Hel2i). This domain is the workhorse of the protein, responsible for:
- **RNA Binding:** The helicase domain, together with the CTD, forms a clamp around the RNA duplex. It specifically recognizes the sugar-phosphate backbone and the unique structural features of dsRNA.
- **ATP Binding and Hydrolysis:** The Walker A and Walker B motifs within Hel1 and Hel2 coordinate ATP binding and hydrolysis. ATP hydrolysis provides the energy for the conformational changes required for CARD release and for the 5' to 3' translocation of RIGI along the RNA duplex, a process that enhances signaling fidelity.
- **Autoinhibition:** In the absence of RNA, the Hel2i domain interacts with the CARDs, stabilizing the closed, inactive conformation.
### 2.3 C-Terminal Domain (CTD) and Repressor Domain (RD) (aa 790-925)
The C-terminal domain is a unique, globular fold that serves dual functions:
- **RNA Ligand Recognition:** The CTD contains a basic, positively charged pocket that specifically recognizes the **5'-triphosphate (5'ppp) moiety** of viral RNA. This is a critical feature of self/non-self discrimination, as host mRNAs are typically capped or processed to remove 5'ppp. The CTD also makes contacts with the RNA duplex backbone, contributing to the high-affinity binding of RIGI to its ligands. It recognizes blunt-ended, short dsRNA (typically 19-21 base pairs) with a 5'ppp group.
- **Repressor Domain (RD):** The CTD also functions as an internal repressor. In the absence of a suitable ligand, the RD interacts with the CARDs and the helicase domain, maintaining the protein in an autoinhibited "closed" conformation. This prevents aberrant activation of the signaling cascade in the absence of infection.
### 2.4 Interactive 3D Visualizer
To explore the three-dimensional architecture of the RIGI protein, including its domain organization and ligand-binding pockets, use the interactive visualizer below.
[Interactive 3D Protein Visualizer: Load RIGI (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O95786)
## 3. Cellular Signaling Pathways & Molecular Function
### 3.1 Ligand Recognition and the "Open" Conformation
In resting cells, RIGI exists in an autoinhibited conformation. Viral infection introduces non-self RNA into the cytoplasm. The primary ligands for RIGI are:
- **Short dsRNA with a 5'-triphosphate (5'ppp) group:** This is the canonical "molecular signature" of many RNA viruses, including influenza A virus, Sendai virus, and respiratory syncytial virus (RSV) [3, 13, 14].
- **Long dsRNA:** RIGI can also bind to longer dsRNA molecules, particularly those with complex secondary structures.
- **RNA with specific sequence features:** Recent evidence suggests RIGI can also recognize specific RNA sequences, such as poly-U/UC-rich motifs found in the hepatitis C virus (HCV) genome.
Binding of RNA to the CTD and helicase domain triggers a conformational change. ATP binding and hydrolysis drive the protein into a fully "open" conformation, releasing the CARDs from their intramolecular sequestration.
### 3.2 Signal Transduction via MAVS
Once released, the CARDs of RIGI are subject to K63-linked polyubiquitination by the E3 ligase TRIM25. This ubiquitination is essential for the high-affinity interaction of RIGI with the CARD domain of MAVS. The RIGI-CARD/MAVS-CARD interaction nucleates the polymerization of MAVS into large, prion-like aggregates on the mitochondrial outer membrane. This aggregation is a critical signal amplification step, creating a signaling platform that recruits downstream effector proteins.
The MAVS signalosome recruits TNF receptor-associated factors (TRAFs), particularly TRAF2, TRAF5, and TRAF6, as well as the kinases TBK1 (TANK-binding kinase 1) and IKKε (IκB kinase ε). These kinases phosphorylate and activate the transcription factors **IRF3** and **IRF7**. Simultaneously, the IKK complex (IKKα, IKKβ, IKKγ/NEMO) is activated, leading to the phosphorylation and degradation of IκBα, which releases the NF-κB transcription factor (p50/p65) for nuclear translocation [11].
### 3.3 Transcriptional Output and the Antiviral State
The coordinated activation of IRF3/7 and NF-κB leads to the transcriptional induction of hundreds of genes, including:
- **Type I and Type III Interferons (IFN-α/β and IFN-λ):** These are the primary antiviral cytokines, which act in an autocrine and paracrine manner to establish an antiviral state in infected and neighboring cells.
- **Pro-inflammatory Cytokines:** TNF-α, IL-6, IL-1β, and CXCL8 (IL-8) are induced, promoting inflammation and recruiting immune cells to the site of infection [13].
- **Interferon-Stimulated Genes (ISGs):** Hundreds of ISGs are induced, including protein kinase R (PKR), 2'-5'-oligoadenylate synthetase (OAS) family members, and Mx proteins, which directly inhibit viral replication [15, 16].
- **Chemokines:** CXCL10, CCL5, and other chemokines are secreted to attract natural killer (NK) cells, T cells, and other immune effectors.
### 3.4 Regulatory Feedback Loops and Post-Translational Modifications
RIGI signaling is tightly regulated to prevent excessive inflammation and autoimmunity. Multiple layers of regulation exist:
- **Transcriptional Regulation:** As mentioned, IFN signaling upregulates *RIGI* expression, creating a positive feedback loop. However, this is counterbalanced by the induction of negative regulators.
- **Post-Translational Modifications (PTMs):**
- **Ubiquitination:** K63-linked ubiquitination by TRIM25 and MEX3C activates RIGI [10]. Conversely, K48-linked ubiquitination by E3 ligases like RNF125 targets RIGI for proteasomal degradation. Deubiquitinases (DUBs) such as USP4 remove K48-linked chains, stabilizing RIGI and enhancing signaling [17].
- **ISGylation:** Conjugation of ISG15 (an ISG) to RIGI can modulate its activity, either positively or negatively depending on the context [18].
- **Phosphorylation:** Protein kinase C (PKC) family members can phosphorylate the CARDs, inhibiting RIGI activation. Dephosphorylation by protein phosphatase 1 (PP1) is required for signaling.
- **Protein-Protein Interaction Inhibitors:** Several cellular proteins negatively regulate RIGI signaling. For example, SEC14L1 has been shown to interact with RIGI and suppress its antiviral signaling [19]. OLFML3, a secreted glycoprotein, has also been identified as a negative regulator of RIG-I signaling during RNA virus infection [20]. The splice variant RIG-I-S acts as a dominant-negative inhibitor [8].
### 3.5 Protein-Protein Interaction Network
The RIGI signaling node is central to a complex network of protein-protein interactions. Key interactors include:
- **Positive Regulators:** TRIM25, MEX3C [10], MAVS, TBK1, IKKε, CHID1 [1], USP4 [17].
- **Negative Regulators:** SEC14L1 [19], OLFML3 [20], RNF125, PKC-α/β.
- **Viral Antagonists:** Influenza NS1 [2], Paramyxovirus V proteins [3], Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF64 [4], HSV-1 UL16 [5].
```mermaid
sequenceDiagram
participant Virus as "Viral dsRNA (5'ppp)"
participant RIGI as "RIGI (Cytosolic)"
participant TRIM25 as "TRIM25 (E3 Ligase)"
participant MAVS as "MAVS (Mitochondria)"
participant TBK1 as "TBK1/IKKε"
participant IRF3 as "IRF3/NF-κB"
participant Nucleus as "Nucleus"
Virus->>RIGI: Binds to CTD & Helicase
activate RIGI
RIGI->>RIGI: ATP Hydrolysis & Conformational Change
TRIM25->>RIGI: K63-Linked Ubiquitination
RIGI->>MAVS: CARD-CARD Interaction
activate MAVS
MAVS->>MAVS: Prion-like Aggregation
MAVS->>TBK1: Recruitment & Activation
activate TBK1
TBK1->>IRF3: Phosphorylation
activate IRF3
IRF3->>Nucleus: Translocation
activate Nucleus
Nucleus->>Nucleus: Transcription of IFN-β & ISGs
deactivate Nucleus
deactivate IRF3
deactivate TBK1
deactivate MAVS
deactivate RIGI
```
## 4. Pathogenic Hotspot Mutations & Clinical Differentials
While germline mutations in *RIGI* are rare, they are associated with significant clinical phenotypes, primarily immunodeficiency and autoimmunity. Somatic mutations and altered expression are more frequently observed in cancers.
### 4.1 Germline Mutations and Primary Immunodeficiency
Loss-of-function mutations in *RIGI* are linked to an increased susceptibility to severe viral infections, particularly respiratory viruses like influenza and RSV [13]. These mutations often cluster in the helicase domain or the CTD, impairing RNA binding or ATP hydrolysis.
- **Helicase Domain Mutations:** Missense mutations in the Walker A motif (e.g., p.Lys270Glu) abolish ATPase activity, rendering the protein signaling-incompetent.
- **CTD Mutations:** Mutations in the RNA-binding pocket of the CTD (e.g., p.His847Arg) disrupt 5'ppp RNA recognition, preventing ligand-induced activation.
- **CARD Mutations:** Mutations in the CARDs (e.g., p.Arg71Cys) can disrupt TRIM25-mediated ubiquitination or MAVS interaction, blocking signal transduction.
### 4.2 Altered Expression in Autoimmune Diseases
Dysregulated RIGI expression or signaling is implicated in the pathogenesis of autoimmune diseases. Aberrant or sustained activation of RIGI by endogenous RNA ligands can lead to excessive type I IFN production, a hallmark of diseases like Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). Studies have shown altered methylation of genes in the IFN pathway, including OAS2 and OAS3, which are downstream effectors of RIGI signaling, in SLE and RA patients [15, 16]. This suggests that epigenetic dysregulation of the RIGI pathway contributes to the chronic inflammation seen in these conditions [6, 7].
### 4.3 Somatic Alterations in Cancer
The role of RIGI in cancer is context-dependent, acting as both a tumor suppressor and a promoter of an immunosuppressive microenvironment.
- **Tumor Suppressor Function:** In many solid tumors, RIGI expression is silenced via promoter hypermethylation. Loss of RIGI allows tumor cells to evade immune surveillance. Restoring RIGI expression or activating it with agonists has been shown to induce tumor cell apoptosis and enhance anti-tumor immunity [4, 5, 6].
- **Pro-tumorigenic Function:** In some contexts, chronic RIGI signaling can promote inflammation, which may contribute to tumor initiation and progression. For example, in glioblastoma (GBM), the tumor microenvironment is highly immunosuppressive. However, recent research has shown that agonist activation of RIG-I in tumor-associated macrophages (TAMs) can reprogram them from an immunosuppressive (M2) to an immunostimulatory (M1) phenotype, enhancing the efficacy of checkpoint immunotherapy [4, 5].
### 4.4 Clinical Differentials
The clinical presentation of RIGI deficiency overlaps with other primary immunodeficiencies affecting the type I IFN pathway, including defects in TLR3, TLR7, TLR8, and UNC93B1. Genetic testing is required for a definitive diagnosis. The clinical differential should include:
- Severe or recurrent viral infections (influenza, RSV, HSV-1 encephalitis).
- Susceptibility to severe COVID-19 [8].
- Atypical presentations of autoimmune diseases with high type I IFN signatures.
## 5. Host-Pathogen & Viral Interactions
Given its central role in antiviral defense, RIGI is a major target for viral immune evasion. Viruses have evolved multiple strategies to antagonize RIGI signaling, targeting nearly every step of the pathway.
### 5.1 Viral Antagonists of RIGI
- **Influenza A Virus NS1 Protein:** The NS1 protein is a multifunctional virulence factor. It directly binds to RIGI and inhibits its activation. NS1 has been shown to block RIGI-mediated activation of the noncanonical NF-κB pathway and p52/RelB-dependent gene expression in lung epithelial cells [2]. It also sequesters dsRNA, preventing it from being sensed by RIGI.
- **Paramyxovirus V Proteins:** The V proteins of paramyxoviruses (e.g., Sendai virus, human parainfluenza virus) bind to the helicase domain of RIGI and MDA5, inhibiting their ATPase activity and downstream signaling. A single arginine residue in the V protein can distinguish between MDA5 and RIGI, highlighting the specificity of these interactions [3]. Sendai virus C proteins also inhibit RIGI-dependent activation of the IFN-β promoter [14].
- **Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF64:** KSHV encodes a deubiquitinase, ORF64, which removes the activating K63-linked polyubiquitin chains from RIGI, thereby inhibiting its signaling [4].
- **Herpes Simplex Virus 1 (HSV-1) UL16:** The tegument protein UL16 of HSV-1 suppresses innate immunity by downregulating MAVS abundance via mitophagy, effectively removing the essential adaptor protein from the signaling pathway [5].
- **Enterovirus Proteases:** Enteroviruses (e.g., EV71) encode proteases that cleave MAVS, RIGI, and TRIM25, leading to their degradation and inhibition of the pathway. They also downregulate miR-526a, which normally enhances RIGI-dependent innate immune responses [9, 10].
- **Human Metapneumovirus (HMPV) Phosphoprotein:** The phosphoprotein of HMPV interferes with RIGI and TLR7 signaling, contributing to the weak innate immune response observed during infection [11].
- **Respiratory Syncytial Virus (RSV):** RSV infection is associated with reduced antiviral gene expression, including RIGI, in peripheral blood, which correlates with severe hypoxemia in infected children [13].
### 5.2 Bacterial Interactions
RIGI is not exclusively a viral sensor. It can also recognize bacterial RNA. For example, *Shigella flexneri* RNA can be sensed by RIGI in the cytosol of infected cells. IFN-γ inhibits the cytosolic replication of *S. flexneri* via a mechanism that requires RIGI, demonstrating a role for RIGI in antibacterial immunity [12].
## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors
The central role of RIGI in both antiviral immunity and anti-tumor immunity makes it an attractive therapeutic target. The therapeutic strategy depends on the disease context: activation for cancer and viral infection, and inhibition for autoimmune diseases.
### 6.1 RIGI Agonists for Cancer Immunotherapy
The most advanced therapeutic application of RIGI modulation is in oncology. The goal is to activate RIGI within the tumor microenvironment to induce an innate immune response that overcomes local immunosuppression and promotes adaptive anti-tumor immunity.
- **RNA-Based Agonists:** Synthetic RNA molecules that mimic viral 5'ppp-dsRNA are potent RIGI agonists. These include:
- **5'ppp-dsRNA:** The canonical RIGI ligand, which has shown efficacy in preclinical models.
- **SLR (Stem-Loop RNA) agonists:** These are short, chemically synthesized hairpin RNAs that are potent and specific RIGI activators.
- **Mechanism of Action:** RIGI activation in tumor cells directly induces apoptosis. In immune cells, particularly dendritic cells (DCs) and macrophages, RIGI activation leads to their maturation and the production of type I IFNs and pro-inflammatory cytokines. This creates a "hot" tumor microenvironment, making tumors more susceptible to immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1).
- **Clinical Evidence:** Preclinical studies have demonstrated that RIGI agonist activation of tumor-associated macrophages enhances anti-tumor immunity and therapeutic response in glioblastoma (GBM) [4, 5]. Furthermore, bifunctional siRNAs that combine TGF-β1 silencing with RIGI activation have shown therapeutic efficacy in pancreatic cancer models [6]. The combination of RIGI agonists with checkpoint inhibitors is a particularly promising strategy.
### 6.2 RIGI Agonists as Vaccine Adjuvants
RIGI agonists are also being explored as vaccine adjuvants. By activating the innate immune system, they can enhance the magnitude and quality of the adaptive immune response to co-administered antigens. This is particularly relevant for mRNA vaccines, where the mRNA itself can act as a RIGI ligand [13].
### 6.3 RIGI Inhibitors for Autoimmune and Inflammatory Diseases
In contrast, for autoimmune diseases characterized by excessive type I IFN production, RIGI inhibitors could be beneficial. Small-molecule inhibitors of the RIGI ATPase or helicase activity are in early-stage development. These molecules aim to block the activation of RIGI by endogenous RNA ligands, thereby reducing pathological inflammation [14].
### 6.4 Pharmacogenomic Considerations
Genetic variation in *RIGI* and its signaling partners (e.g., *MAVS*, *TRIM25*) could influence the response to RIGI-targeted therapies. For example, tumors with silenced *RIGI* expression may require combination therapies that first restore RIGI expression (e.g., with demethylating agents) before agonist treatment can be effective. Similarly, polymorphisms in the *RIGI* promoter that affect its inducibility could impact the efficacy of IFN-based therapies.
## 7. Bioinformatic Resources & Database Accessions
The following table provides key database accessions for the RIGI gene and protein.
| **Database** | **Identifier** | **Description** |
| :--- | :--- | :--- |
| **NCBI Gene** | 23586 | Gene ID for *RIGI* (DDX58) |
| **Ensembl** | ENSG00000107201 | Ensembl Gene ID for *RIGI* |
| **UniProt** | O95786 | Primary protein accession for human RIGI |
| **RCSB PDB** | 4AYA, 2ZA5, 3OG8, 3NCY | Representative crystal structures of RIGI domains and complexes |
| **HGNC** | 2910 | HUGO Gene Nomenclature Committee symbol |
| **OMIM** | 609631 | Online Mendelian Inheritance in Man entry |
| **ClinVar** | Gene: 23586 | Database of clinically relevant human variants |
| **STRING** | 9606.ENSP00000358857 | Protein-protein interaction networks |
| **BioGRID** | 112345 | Biological General Repository for Interaction Datasets |
| **Gene Ontology (GO)** | GO:0003725 (dsRNA binding), GO:0005524 (ATP binding), GO:0039529 (RIG-I signaling pathway), GO:0005737 (cytoplasm) | Functional annotations |
## Related Clinical & Scientific Guides
* [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway)
* [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway)
* [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway)
## References
[1] Pal, A., Pal, A., & Baviskar, P. (2020). Molecular characterization of RIGI, TLR7 and TLR3 as immune response gene of indigenous ducks in response to Avian influenza. *bioRxiv*. URL: https://www.semanticscholar.org/paper/6cf6e5d34c2020d2ff40981f3d6a16b21f7e0d38
[2] Pal, S., Banerjee, S., Pal, A., Kalita, D., Batabyal, S., Debnath, M., ... & Pal, A. (2022). Role of RIGI, MDA5 and interferon alpha of duck in Duck Plague infection – a novel report. *bioRxiv*. URL: https://www.semanticscholar.org/paper/af779fe9cf081d78fa577366284f37eae74d41e1
[3] Li, W., Chen, H., Sutton, T., Obadan, A. O., & Pérez, D. (2014). Interactions between the Influenza A Virus RNA Polymerase 1 Components and Retinoic Acid-Inducible Gene I. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/48cd1c8b549a18ec781293ab42d6e5f2ca03033e
[4] Klein, C., & Hartl, D. (2013). Analysis of Toll-like receptors and retinoic-acid-inducible gene-I (RIGI)-like helicases in human neutrophils and HL 60 cells. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/91e0cf6fd3bde2e40ea5f887ddfaaaaabcf56fb2
[5] Rückle, A., Haasbach, E., Julkunen, I., Planz, O., Ehrhardt, C., & Ludwiga, S. (2012). The NS1 Protein of Influenza A Virus Blocks RIGI-Mediated Activation of the Noncanonical NF-κB Pathway and p52/RelB-Dependent Gene Expression in Lung Epithelial Cells. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/92d7b75ab3fdc18f971ec694eaf439556f8f888c
[6] Rigi Yousefabadi, E., Ourang, Z., Gharibdoost, F., Faezi, S., Saatchi, M., Gholami, D., ... & Khorram Khorshid, H. R. (2025). Hypomethylation of OAS2 and OAS3 Gene Promoters: Insights into the Pathogenesis of Systemic Lupus Erythematosus. *Iranian journal of immunology : IJI*. URL: https://www.semanticscholar.org/paper/09bd40d972548bc53ca9bc28250b047a580c5670
[7] Jiang, Z., Tian, J., Parroche, P., Schickli, J., Monks, B. G., Ulbrandt, N., ... & Fitzgerald, K. A. (2009). Cell Type-Specific Recognition of Human Metapneumoviruses (HMPVs) by Retinoic Acid-Inducible Gene I (RIGI) and TLR7. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/5f96f9ae627087ff5ba4236618e23eef9fcb8598
[8] Pita-Martínez, C., Goez-Sanz, C., Virseda-Berdices, A., Gonzalez-Praetorius, A., Mazario-Martín, E., Rodriguez-Mesa, M., ... & Resino, S. (2024). Reduced antiviral gene expression and elevated CXCL8 expression in peripheral blood are associated with severe hypoxemia in RSV-infected children. *Frontiers in Immunology*. URL: https://www.semanticscholar.org/paper/96848ac8904830e37f8831381d722cf366149c96
[9] Sharifi-Rigi, A., Heidarian, E., & Amini, S. A. (2019). Protective and anti-inflammatory effects of hydroalcoholic leaf extract of Origanum vulgare on oxidative stress, TNF-α gene expression and liver histological changes in paraquat-induced hepatotoxicity in rats. *Archives of Physiology and Biochemistry*. URL: https://www.semanticscholar.org/paper/decd83db78d4df8d11b76eef86e19d21de2d1380
[10] Nasr, N., Alshehri, A. A., Wright, T. K., Shahid, M., Heiner, B. M., Harman, A., ... & Cunningham, A. (2017). Mechanism of Interferon-Stimulated Gene Induction in HIV-1-Infected Macrophages. *Journal of Virology*. URL: https://www.semanticscholar.org/paper/4a87c3f28605390a3a61a1a2bfa2a4f788bc011b
[11] Strähle, L., Marq, J., Brini, A., Hausmann, S., Kolakofsky, D., & Garcin, D. (2017). Activation of the beta interferon promoter by unnatural Sendai virus infection requires RIGI and is inhibited by viral C proteins. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/82785b89ff287fa59810cff8a987fed5efba7e76
[12] Rezaei, F., Javid, A., Armand, R., Rigi, G., Ranjbaran, H., Armand, N., & Pourjafar, H. (2026). Mir-182 Effects on PTEN and FOXO1 Gene Expression in SW480 Metastatic Colorectal Cancer Cells. *Advances in Cancer Biology - Metastasis*. URL: https://www.semanticscholar.org/paper/438b22d09ad9a8a6a816136cdb770150651fea85
[13] Gholami, D., Ourang, Z., Saatchi, M., Rigi Yousefabadi, E., Esmaeilzadeh, E., Akhlaghi, M., ... & Khorram Khorshid, H. K. (2026). Hypomethylation of the Human OAS2 Gene in Blood Cells as a Potential Biomarker for Rheumatoid Arthritis: Findings from an Iranian Case-control Study. *Archives of Iranian medicine*. URL: https://www.semanticscholar.org/paper/9a6a9f7958ee2a9c889e1b5c9d77a798a947abc0
[14] Heutinck, K., Kassies, J., Florquin, S., Berge, I., Hamann, J., & Rowshani, A. (N/A). SerpinB9 expression in human renal tubular epithelial cells is induced by triggering of the viral dsRNA sensors TLR3, MDA5 and RIGI. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/d034ac944298c9167b2f5f0db7217e77cb6b8d1d
[15] Bertolusso, R., Lipniacki, T., Brasier, A., & Kimmel, M. (N/A). Modeling the Dynamics of the RIGI-MAVS/NF-κB/IRF3 Signaling Pathway. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/602823b46b504443a2b412f86e49c7babd1decc5
[16] Oleynik, V. A., Plotnikova, M., Yolshin, N. D., Romanovskaya-Romanko, E., & Klotchenko, S. (2025). Development and approbation of a quantitative PCR system for studying the expression of endosomal receptors and cytosolic nucleic acid sensors in mice. *Medical academic journal*. URL: https://www.semanticscholar.org/paper/08a76718b78fee8b8c92e7e2382cd6810dbd43df
[17] Li, X., Zhou, Y., Wei, J., Sun, W., Fan, L., & Yan, J. (2025). Unlocking the Puzzle of Mammalian Transfection: The Role of the RNA-sensing-Mediated Interferon Response in the Cellular Defense Against Foreign DNA Intrusion. *International Journal on Biological Sciences*. URL: https://www.semanticscholar.org/paper/09cb1021cb5a8aae14a7587fba292a22c8750d5c
[18] Bylinska, A., Smith, M., Lu, R., Jones, B., Guthridge, C., Macwana, S., ... & Guthridge, J. (2025). Integrative omics identify increase of pattern recognition and ubiquitin related signatures specific to ANA+ at risk of SLE individuals. *Journal of Immunology*. URL: https://www.semanticscholar.org/paper/a12a90fbb646742c26df6fa9add095f4be620ad3
[19] Xu, H., Lee, S., Leser, F., Federova, O., Lu, P., Song, E., ... & Thomas, J. (2026). Agonist activation of RIG-I+tumor associated macrophages enhances anti-tumor immunity and therapeutic response in glioblastoma. *Cancer Research*. URL: https://www.semanticscholar.org/paper/105be79fe6dfcf6465ad0a9a07dd069ff13018e3
[20] Xu, H., Lee, S., Leser, F., Fedorova, O., Lu, P., Song, E., ... & Thomas