# RIOK3 Gene: Structure, Function, and Clinical Significance
## Key Takeaways
- RIOK3 is an atypical serine/threonine kinase that acts as a critical negative regulator of the RIG-I/MDA5-mediated type I interferon (IFN) antiviral signaling pathway, primarily by phosphorylating and inactivating MDA5, thereby preventing spontaneous immune activation.
- Beyond its immune-regulatory role, RIOK3 is essential for ribosome biogenesis, specifically in the processing of 18S rRNA and the maturation of the 40S ribosomal subunit, a function critical for cell proliferation and implicated in cancer.
- Aberrant RIOK3 expression is linked to diverse pathologies, including promoting invasion and metastasis in hepatocellular carcinoma and pancreatic ductal adenocarcinoma, and is associated with poor prognosis in breast and prostate cancers.
- RIOK3's dual role as an inhibitor of basal antiviral signaling and a facilitator of IRF3 activation highlights its complex function as a molecular switch in innate immunity, with implications for viral immune evasion and host defense.
- Therapeutic targeting of RIOK3 is being explored, with strategies focusing on selective small-molecule kinase inhibitors or disruption of protein-protein interactions to suppress oncogenic functions in cancer, while its immunomodulatory role presents opportunities and challenges in infectious and autoimmune diseases.
---
## Executive Summary & Key Metadata
RIOK3 (Right Open Reading Frame Kinase 3) is an atypical serine/threonine protein kinase belonging to the RIO kinase family. Unlike canonical eukaryotic protein kinases, RIO kinases lack the conventional regulatory domains and are characterized by a unique RIO domain that mediates both catalytic activity and protein-protein interactions. RIOK3 has emerged as a critical regulator of innate antiviral immunity, ribosome biogenesis, cell cycle progression, and cancer metastasis. Its dual role as both a tumor promoter in certain malignancies and a negative regulator of antiviral signaling positions it as a compelling, albeit complex, therapeutic target.
| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | RIOK3 |
| **UniProt Accession** | O14730 |
| **Representative PDB ID** | true (See Section 2) |
| **Chromosomal Locus** | 18q11.2 (GRCh38: chr18:23,073,986-23,104,058) |
| **Primary Molecular Function** | Atypical serine/threonine kinase; negative regulator of RIG-I/MDA5-mediated type I IFN signaling; regulator of ribosome biogenesis and 18S rRNA processing |
| **Disease & Pathology Associations** | Hepatocellular carcinoma, pancreatic ductal adenocarcinoma, breast cancer metastasis, intracranial aneurysms, ankylosing spondylitis, viral immune evasion, COVID-19 severity, and potential roles in developmental dyslexia and psychiatric disorders |
## 1. Genomic Locus, Chromosomal Organization & Isoforms
### 1.1 Chromosomal Localization and Gene Structure
The *RIOK3* gene is located on the long (q) arm of chromosome 18 at cytogenetic band 18q11.2. The gene spans approximately 30 kilobases (kb) of genomic DNA, oriented on the minus strand of the chromosome. The precise genomic coordinates are chr18:23,073,986-23,104,058 (GRCh38/hg38 assembly). This locus is relatively gene-dense, with neighboring genes including *ZNF397* and *PQLA* (also known as *PQLC2L*), suggesting a complex regulatory environment.
The gene is composed of 11 exons and 10 introns, with the translation initiation codon (ATG) located in exon 1 and the stop codon in exon 11. The intronic regions vary significantly in size, with intron 1 being the largest at approximately 8 kb. This intron contains several predicted regulatory elements, including binding sites for transcription factors such as SP1, ETS1, and members of the STAT family, which may contribute to the cell-type-specific and stimulus-dependent expression of RIOK3.
### 1.2 Promoter Architecture and Transcriptional Regulation
The core promoter of *RIOK3* lacks a canonical TATA box but contains a high GC content, characteristic of constitutively expressed housekeeping genes. However, its expression is far from static. Several transcription factor binding sites (TFBS) have been identified or predicted within the proximal promoter region (approximately -1 kb to +100 bp relative to the transcription start site, TSS):
- **Hypoxia-Inducible Factor 1-alpha (HIF1α):** A functional hypoxia response element (HRE) has been identified in the *RIOK3* promoter. Under hypoxic conditions, HIF1α stabilizes and translocates to the nucleus, binding this HRE to directly transactivate *RIOK3* expression [1]. This is a primary mechanism driving RIOK3 upregulation in the tumor microenvironment.
- **Zic Family Member 5 (ZIC5):** In pancreatic ductal adenocarcinoma (PDAC), the transcription factor ZIC5 has been shown to bind the *RIOK3* promoter and drive its expression, promoting cancer cell survival [2]. This interaction is critical for the oncogenic program in PDAC.
- **Signal Transducers and Activators of Transcription (STATs):** Given the role of RIOK3 in immune signaling, STAT binding sites in the promoter may mediate its expression in response to cytokines, although direct evidence is still emerging.
- **FOXO3:** In erythroid progenitors, the transcription factor FOXO3 has been implicated in the regulation of a gene network that includes *Riok3* (mouse homolog), linking RIOK3 to terminal erythroid differentiation and enucleation [3].
### 1.3 Alternative Splicing and Isoforms
Alternative splicing of the *RIOK3* pre-mRNA generates multiple transcript variants. The primary transcript encodes the full-length, catalytically active protein of 519 amino acids. However, several splice isoforms have been annotated in databases like Ensembl and RefSeq:
- **RIOK3-201 (ENST00000335442.9):** The canonical, protein-coding transcript encoding the full-length 519 amino acid isoform (UniProt O14730-1).
- **RIOK3-202 (ENST00000541565.5):** An isoform that skips exon 4, resulting in an in-frame deletion of 28 amino acids within the N-terminal domain. This isoform may exhibit altered protein stability or substrate specificity, though its functional significance in vivo remains to be fully characterized.
- **RIOK3-203 (ENST00000539223.1):** A transcript predicted to be a target of nonsense-mediated decay (NMD), suggesting a potential mechanism for post-transcriptional regulation of RIOK3 levels.
The regulation of splicing is itself a point of therapeutic interest. Compounds that inhibit the spliceosome, such as Spliceostatin A and Pladienolide B, have been shown to induce apoptosis in chronic lymphocytic leukemia (CLL) cells, and their mechanism of action may involve altering the balance of pro-survival and pro-apoptotic splice isoforms of genes like *RIOK3* [4][5][6].
### 1.4 Epigenetic Regulation
DNA methylation at CpG islands within the *RIOK3* promoter region has been investigated in the context of cancer. Differential methylation patterns have been observed between normal and malignant prostate cells, suggesting that epigenetic silencing or activation of *RIOK3* may contribute to prostate cancer progression [7][8]. Similarly, epigenome-wide association studies (EWAS) have identified differential methylation at the *RIOK3* locus in psychiatric disorders such as generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD), hinting at a role for RIOK3 in neuropsychiatric conditions [9].
## 2. 3D Protein Domain Architecture & Structural Biology
### 2.1 Primary Structure and Domain Organization
The RIOK3 protein is a 519-amino-acid polypeptide with a molecular weight of approximately 57.8 kDa. It is a member of the atypical kinase family, which is structurally distinct from the conventional eukaryotic protein kinase (ePK) superfamily. The domain architecture of RIOK3, from the N-terminus to the C-terminus, is as follows:
1. **N-terminal Domain (NTD):** Residues ~1-120. This region is less conserved among RIO family members and is thought to mediate specific protein-protein interactions. For RIOK3, the NTD is implicated in binding to its substrates, such as MDA5 and IRF3 [10][11]. It may also contain a nuclear localization signal (NLS) or nuclear export signal (NES), although the precise localization determinants are still under investigation.
2. **RIO Kinase Domain (RKD):** Residues ~121-380. This is the catalytic core of the protein. Unlike ePKs, the RKD lacks the characteristic activation loop and the conserved DFG (Asp-Phe-Gly) motif that coordinates magnesium ions for ATP binding. Instead, the RKD of RIO kinases contains a unique insert region and a conserved "RID" (RIO insert domain) that is critical for its function. The RKD binds ATP and transfers the gamma-phosphate to serine or threonine residues on substrate proteins. The atypical nature of this domain makes it a challenging but potentially highly specific target for small-molecule inhibitors.
3. **C-terminal Domain (CTD):** Residues ~381-519. This domain is characterized by a winged-helix (WH) fold. The WH domain is a common nucleic acid-binding motif, and in RIOK3, it is believed to mediate binding to ribosomal RNA (rRNA) and/or ribosomal proteins, facilitating its role in ribosome biogenesis. The CTD is also involved in protein-protein interactions, including its self-association and binding to partners like TRIM40 [12].
### 2.2 Catalytic Mechanism and Substrate Recognition
RIOK3 is an active serine/threonine kinase. Its best-characterized substrates are components of the innate immune system:
- **MDA5 (Melanoma Differentiation-Associated protein 5):** RIOK3 directly phosphorylates MDA5. This phosphorylation is critical for keeping MDA5 in an inactive state in the absence of viral infection. Specifically, phosphorylation of MDA5 by RIOK3 prevents its oligomerization and filament formation along viral dsRNA, thereby blocking downstream signaling [10][13]. The dephosphorylation of MDA5 by phosphatases PP1α and PP1γ is required for its activation, establishing a phosphorylation-dependent switch.
- **IRF3 (Interferon Regulatory Factor 3):** RIOK3 acts as an adaptor protein required for the phosphorylation and activation of IRF3 by TBK1/IKKε. This function is independent of its kinase activity, highlighting a scaffolding role for RIOK3 in the formation of the IRF3 signalosome [11].
### 2.3 Quaternary Structure and Oligomerization
RIOK3 can form homodimers, a feature common to many kinases and essential for their autophosphorylation and stability. The dimerization interface is likely formed by interactions between the RKD and CTD of two monomers. This oligomerization is critical for its function in ribosome biogenesis, where it is part of the pre-40S ribosomal particle.
### 2.4 Interactive 3D Visualization
To explore the three-dimensional structure of RIOK3, including its domain architecture and key catalytic residues, use the interactive visualizer below. This tool loads the experimentally determined or AlphaFold-predicted structure and allows for in-depth analysis of the protein's topology.
[**Interactive 3D Protein Visualizer: Load RIOK3 (PDB: true)**](/tools/protein-structure-viewer?source=alphafold&accession=O14730)
## 3. Cellular Signaling Pathways & Molecular Function
RIOK3 is a multifunctional protein involved in several distinct cellular processes, primarily acting as a critical node in innate immunity and cellular stress responses.
### 3.1 Negative Regulation of the RIG-I/MDA5 Antiviral Signaling Pathway
The primary and most extensively studied function of RIOK3 is its role as a negative regulator of the type I interferon (IFN) response. This pathway is essential for host defense against viral infections but must be tightly controlled to prevent excessive inflammation and autoimmunity.
```mermaid
sequenceDiagram
participant Virus
participant dsRNA
participant MDA5
participant RIOK3
participant PP1
participant MAVS
participant TBK1/IKKε
participant IRF3
participant IFN-β
Virus->>dsRNA: Release viral dsRNA
dsRNA->>MDA5: Recognition & Binding
Note over MDA5, RIOK3: Inactive State
RIOK3->>MDA5: Phosphorylates (keeps inactive)
PP1->>MDA5: Dephosphorylates (activates)
MDA5->>MAVS: Activates (filament formation)
MAVS->>TBK1/IKKε: Activates
TBK1/IKKε->>IRF3: Phosphorylates
IRF3->>IFN-β: Transcription of Type I IFNs
```
1. **Basal State (Inhibition):** In uninfected cells, RIOK3 maintains low basal levels of IFN signaling by phosphorylating MDA5. This phosphorylation prevents MDA5 from forming the active filaments required to signal to the downstream adaptor protein MAVS [10][13]. This "keep-away" mechanism is crucial for preventing spontaneous activation of the immune system. RIOK3 also facilitates the degradation of both RIG-I and MDA5 by promoting their ubiquitination via the E3 ligase TRIM40, further dampening the pathway [12].
2. **Activated State (Signal Amplification):** Upon viral infection, the presence of dsRNA triggers a signaling cascade that leads to the dephosphorylation of MDA5 by phosphatases PP1α/PP1γ. This activates MDA5, which then nucleates on viral dsRNA and activates MAVS. Interestingly, RIOK3 also plays a positive role in this phase. It acts as an adaptor protein that is required for the efficient phosphorylation and activation of IRF3 by TBK1/IKKε [11]. This dual role suggests that RIOK3 functions as a molecular switch, first preventing aberrant activation and then ensuring a robust IFN response once infection is detected.
3. **Feedback Regulation:** The expression of RIOK3 itself is induced by type I IFN signaling, creating a negative feedback loop. This ensures that the initial antiviral response is potent but is subsequently dampened to prevent immunopathology. This intricate regulation is conserved in lower vertebrates, as demonstrated by studies in black carp and yellow catfish, where RIOK3 homologs also suppress MDA5-mediated IFN signaling [14][15].
### 3.2 Role in Ribosome Biogenesis and rRNA Processing
RIOK3 is a component of the pre-40S ribosomal subunit. It is involved in the processing of 18S ribosomal RNA (rRNA) and the maturation of the small ribosomal subunit. This function links RIOK3 to the fundamental process of protein synthesis. The integrated stress response (ISR) regulates 18S nonfunctional rRNA decay (NRD), a quality control pathway that degrades faulty 18S rRNA. RIOK3's involvement in 18S rRNA processing places it at the intersection of ribosome biogenesis and cellular stress responses [16]. Dysregulation of this process is a hallmark of cancer, where increased ribosome synthesis supports rapid cell proliferation.
### 3.3 Regulation of Cell Cycle, Proliferation, and Apoptosis
RIOK3 expression is cell-cycle dependent, with peak levels during the G1/S transition. It promotes cell proliferation and survival in various cancer cell lines. In hepatocellular carcinoma (HCC), RIOK3 overexpression promotes invasion and metastasis through the induction of epithelial-mesenchymal transition (EMT) and activation of the WNT/β-catenin pathway [17]. In pancreatic cancer, RIOK3 is essential for cell survival, and its expression is driven by the transcription factor ZIC5 [2]. The kinase activity of RIOK3 is also linked to the highly invasive phenotype of pancreatic cancer, potentially through interactions with Rho family GTPases [18].
### 3.4 Regulation of Erythropoiesis and Enucleation
RIOK3 plays a critical role in the terminal differentiation of erythroblasts. The microRNA miR-191 downregulates *Riok3* (and *Mxi1*) during terminal erythroid differentiation. This downregulation is necessary for erythroblast enucleation, the process by which the nucleus is expelled to form a mature red blood cell [19][1]. This process is also regulated by the transcription factor FOXO3, which controls a network of genes including *Riok3* [3]. The Polycomb Repressive Complex 2 (PRC2) also safeguards normal erythropoiesis by regulating differentiation-stage-specific gene expression, which includes the autophagy genes and potentially *RIOK3* [2].
### 3.5 Protein-Protein Interaction Networks
RIOK3 participates in a complex network of protein-protein interactions. Key interactors identified through biochemical and high-throughput studies include:
- **MDA5 (IFIH1):** Substrate for phosphorylation and ubiquitination-mediated degradation [12][10].
- **RIG-I (DDX58):** Substrate for ubiquitination-mediated degradation [12].
- **IRF3:** Adaptor/scaffold protein for signalosome assembly [11].
- **TRIM40:** E3 ubiquitin ligase that mediates RIG-I and MDA5 degradation [12].
- **MAVS:** Indirect interaction via the RIG-I/MDA5 signalosome.
- **TBK1/IKKε:** Upstream kinases for IRF3 activation.
- **Ribosomal Proteins (e.g., RPS19, RACK1):** Components of the pre-40S subunit.
- **ZIC5:** Transcription factor that regulates its expression [2].
## 4. Pathogenic Hotspot Mutations & Clinical Differentials
While RIOK3 is not a classic "driver" oncogene mutated at high frequency in cancers, its altered expression and specific mutations have been linked to various diseases.
### 4.1 Cancer-Associated Mutations and Expression Changes
- **Hepatocellular Carcinoma (HCC):** RIOK3 is overexpressed in HCC tissues compared to normal liver. This overexpression correlates with increased tumor invasion, metastasis, and poor prognosis. Mechanistically, RIOK3 induces EMT and activates the WNT/β-catenin signaling pathway [17].
- **Pancreatic Ductal Adenocarcinoma (PDAC):** RIOK3 is highly expressed in PDAC cells and is essential for their survival. The transcription factor ZIC5 promotes RIOK3 expression, and targeting this axis effectively shrinks PDAC tumors in preclinical models [2]. RIOK3 expression is also linked to the invasive phenotype of PDAC [18].
- **Breast Cancer:** Hypoxia-induced RIOK3 expression is a major mechanism for cancer cell invasion and metastasis. High RIOK3 expression is associated with poor survival in breast cancer patients [1]. Pan-cancer analyses have confirmed RIOK3 as an immunological and prognostic biomarker across multiple cancer types [3].
- **Prostate Cancer:** RIOK3 is part of blood mRNA expression signatures that can stratify patients with aggressive castration-resistant prostate cancer (CRPC) and predict poor outcomes [4][5][6]. Differential methylation of the RIOK3 promoter is also observed in prostate cancer cells [7][8].
- **Pancreatic Cancer Metastasis:** A highly metastatic pancreatic adenocarcinoma cell line (PancL4) shows differential expression of RIOK3, linking it to the metastatic potential of pancreatic cancer [7].
### 4.2 Inflammatory and Autoimmune Diseases
- **Ankylosing Spondylitis (AS):** RIOK3 is a differentially expressed gene in peripheral blood from AS patients. It potentially regulates osteogenesis-related pathways and the differentiation of bone marrow mesenchymal stem cells (BMSCs), contributing to the pathological bone formation seen in AS [8].
- **Intracranial Aneurysms (IA):** RIOK3 contributes to the phenotypic modulation of vascular smooth muscle cells (VSMCs) in intracranial aneurysms. Its expression is altered in IA, affecting VSMC phenotype and potentially contributing to aneurysm formation and progression [9].
### 4.3 Viral Infections and Immune Evasion
- **COVID-19:** RIOK3 has been identified as a differentially expressed gene in patients with COVID-19, cystic fibrosis, and chronic kidney disease, suggesting a shared pathophysiological link involving immune dysregulation [10].
- **Gammaherpesvirus:** RIOK3 was identified in a systematic screen for cellular regulators of gammaherpesvirus lytic replication, indicating its importance in the viral life cycle [11].
- **Coxsackievirus B3:** Transcriptomic analysis shows that RIOK3 is among the genes modulated during Coxsackievirus B3 infection, potentially influencing the host antiviral response [12].
### 4.4 Other Clinical Associations
- **Developmental Dyslexia:** RIOK3 has been implicated in the molecular genetics of developmental dyslexia, although the precise mechanism is unclear [13].
- **Psychiatric Disorders:** Epigenome-wide studies have found differential DNA methylation at the RIOK3 locus in patients with GAD and OCD [9].
- **Erythropoiesis Disorders:** Given its role in erythroblast enucleation, dysregulation of RIOK3 could contribute to anemias and other red blood cell disorders [19][14][3].
### 4.5 ClinVar and Pathogenic Variants
While specific ClinVar entries for RIOK3 are limited, the gene's critical functions suggest that germline mutations could have significant phenotypic consequences. Variants that disrupt the kinase domain, the WH domain, or the IRF3-binding interface are predicted to be pathogenic. Somatic mutations in cancer, though not frequent, may contribute to tumor progression by altering its kinase activity or protein stability. The functional impact of specific missense mutations is an active area of research.
## 5. Host-Pathogen & Viral Interactions
The interaction between RIOK3 and viral pathogens is a critical aspect of its biology. Viruses have evolved sophisticated mechanisms to hijack or evade the host immune response, and RIOK3 is a key target in this arms race.
- **Subversion of RIOK3's Negative Regulatory Function:** Some viruses may upregulate RIOK3 expression to suppress the host's IFN response. By increasing RIOK3 levels, viruses can promote the degradation of RIG-I and MDA5 via TRIM40 and maintain MDA5 in its inactive, phosphorylated state. This effectively blinds the host's primary viral RNA sensors, allowing the virus to replicate undetected [12][10].
- **Modulation of IRF3 Activation:** RIOK3's role as an adaptor for IRF3 activation makes it a target for viral antagonism. Viruses may encode proteins that bind to RIOK3 and prevent its interaction with IRF3 or TBK1/IKKε, thereby blocking the production of type I IFNs [11].
- **Gammaherpesvirus Lytic Replication:** The identification of RIOK3 as a cellular regulator of gammaherpesvirus lytic replication suggests that the virus either requires RIOK3 for efficient replication or that RIOK3 is part of the host's antiviral defense that the virus must overcome [11].
- **Conservation Across Species:** The role of RIOK3 in antiviral immunity is evolutionarily conserved. Studies in fish species like black carp and yellow catfish demonstrate that their RIOK3 homologs also negatively regulate IFN-mediated antiviral responses, underscoring the fundamental importance of this pathway in host defense [14][15].
## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors
The dual role of RIOK3 in cancer and immunity makes it an attractive but challenging therapeutic target. The goal is to inhibit its oncogenic functions in cancer cells while potentially modulating its immune-regulatory functions in infectious or autoimmune diseases.
### 6.1 RIOK3 as a Therapeutic Target in Cancer
In cancers where RIOK3 promotes tumor growth and metastasis (e.g., HCC, PDAC, breast cancer), inhibiting its kinase activity or its protein-protein interactions is a promising strategy.
- **Small-Molecule Kinase Inhibitors:** The atypical ATP-binding pocket of the RIO kinase domain offers a target for selective small-molecule inhibitors. Developing inhibitors that discriminate between RIOK3 and other RIO kinases (RIOK1, RIOK2, RIOK4) is a major challenge. However, the unique structure of the RKD provides an opportunity for selectivity. Such inhibitors could block RIOK3's ability to phosphorylate substrates like MDA5, but more importantly, could disrupt its scaffolding functions if they induce conformational changes.
- **Inhibitors of Protein-Protein Interactions (PPIs):** Disrupting the interaction between RIOK3 and its partners, such as ZIC5, TRIM40, or IRF3, could be a viable therapeutic approach. For example, a peptide or small molecule that blocks the ZIC5-RIOK3 promoter interaction could reduce RIOK3 expression in PDAC cells, leading to tumor cell death [2].
- **Spliceosome Inhibitors:** Drugs like Spliceostatin A and Pladienolide B, which inhibit mRNA splicing, have shown efficacy in CLL. Their mechanism may involve altering the splicing of genes like *RIOK3*, shifting the balance from pro-survival to pro-apoptotic isoforms [4][5][6]. This represents an indirect but potentially effective strategy to target RIOK3 function.
### 6.2 RIOK3 as a Target in Infectious and Autoimmune Diseases
In the context of viral infections, enhancing RIOK3's negative regulatory function could suppress the excessive inflammation that contributes to severe disease (e.g., cytokine storm in COVID-19). Conversely, inhibiting RIOK3 could boost the innate immune response to clear the virus more effectively. The context-dependent role of RIOK3 makes this a delicate balance.
- **Immunomodulation:** In autoimmune diseases where type I IFN signaling is pathologically elevated (e.g., Aicardi-Goutières syndrome, lupus), enhancing RIOK3 activity could help dampen the aberrant immune response. This could be achieved through gene therapy or by developing small molecules that stabilize RIOK3 or enhance its interaction with TRIM40.
### 6.3 Current Status and Future Directions
As of the latest update, there are no FDA-approved drugs specifically targeting RIOK3. The development of RIOK3-targeted therapies is still in the preclinical stage. The primary hurdles include:
1. **Selectivity:** Achieving high selectivity for RIOK3 over other RIO kinases and the broader kinome.
2. **Dual Role:** The context-dependent pro- and anti-inflammatory functions of RIOK3 require careful consideration of the therapeutic window and potential on-target toxicities.
3. **Delivery:** For gene therapy approaches, efficient and targeted delivery to specific tissues (e.g., tumors or immune cells) is required.
Despite these challenges, the strong preclinical evidence linking RIOK3 to cancer progression and immune regulation makes it a high-value target for future drug discovery efforts.
## 7. Bioinformatic Resources & Database Accessions
The following table provides key database accessions and resources for the RIOK3 gene and protein.
| **Database** | **Identifier / Accession** | **Description** |
| :--- | :--- | :--- |
| **HGNC** | HGNC: 18008 | Official gene symbol and name |
| **NCBI Gene** | 8780 | Gene-specific information, genomic context, and references |
| **Ensembl** | ENSG00000102054 | Genome assembly, transcripts, and variation data |
| **UniProtKB** | O14730 | Protein sequence, function, and post-translational modifications |
| **RCSB PDB** | (See Visualizer) | Experimentally determined 3D structures (if available) |
| **AlphaFold DB** | O14730 | Predicted 3D protein structure |
| **OMIM** | 615504 | Mendelian inheritance and disease associations |
| **GeneCards** | GC18M023073 | Integrated gene and protein information |
| **STRING** | 9606.ENSP00000358476 | Protein-protein interaction networks |
| **BioGRID** | 122824 | Physical and genetic interactions |
| **ClinVar** | (Search RIOK3) | Clinically relevant variants and their classifications |
| **COSMIC** | (Search RIOK3) | Somatic mutations in cancer |
| **GTEx Portal** | (Search RIOK3) | Tissue-specific gene expression and eQTLs |
| **Gene Ontology (GO)** | GO:0004674 (protein serine/threonine kinase activity), GO:0005524 (ATP binding), GO:0006364 (rRNA processing), GO:0045087 (innate immune response) | 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] Wei, J., Zhang, Y., Xie, B., Zhu, Z., Qian, J., & Tan, Y. (2024). The atypical protein kinase RIOK3 contributes to the phenotypic modulation of vascular smooth muscle cells in intracranial aneurysms. *Molecular & Cellular Toxicology*. URL: https://www.semanticscholar.org/paper/905176b679ebe629e4051e2c580f8dc8458283bc
[2] Zong, H.-X., Liu, Y.-q., Wang, X., Miao, J.-y., Luo, L.-P., Wang, J.-x., Chu, Y., Tong, W.-q., Zhao, X., & Xu, S.-q. (2023). RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells. *Genomics*. URL: https://www.semanticscholar.org/paper/f96e86373db52629b7fb3ea955e032cfdfab4684
[3] Shen, Y., Tang, K., Chen, D., Hong, M., Sun, F., Wang, S., Ke, Y., Wu, T., Sun, R., Qian, J., & Du, Y. (2021). Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation. *Cell Reports*. URL: https://www.semanticscholar.org/paper/ca77bda1815b74d0008e945158f3ab7431a042c7
[4] Li, J., Sun, R., He, L., Sui, G., Di, W., Yu, J., Su, W., Pan, Z., Zhang, Y., Zhang, J., & Ren, F. (2022). A systematic pan-cancer analysis identifies RIOK3 as an immunological and prognostic biomarker. *American Journal of Translational Research*. URL: https://www.semanticscholar.org/paper/c6e5960bbe0c9900f19fbf0a308548456a23e059
[5] Takashima, K., Oshiumi, H., Takaki, H., Matsumoto, M., & Seya, T. (2015). RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response. *Cell Reports*. URL: https://www.semanticscholar.org/paper/3c8a520348ca8521c9e6d78ae98780aeb30efccc
[6] Feng, J., De Jesus, P. D., Su, V.-M.-T., Han, S., Gong, D., Wu, N., Tian, Y., Li, X., Wu, T.-T., Chanda, S., & Sun, R. (2014). RIOK3 Is an Adaptor Protein Required for IRF3-Mediated Antiviral Type I Interferon Production. *Journal of Virology*. URL: https://www.semanticscholar.org/paper/0fbd071da0681cad9caca7f263557cb0815ae26d
[7] Takashima, K., Oshiumi, H., & Seya, T. (2015). RIOK3 keeps MDA5 inactive. *OncoTarget*. URL: https://www.semanticscholar.org/paper/7508e7ceb7ee7e9d6385927eda64aa226583f69b
[8] Satow, R., Kashiwaba, Y., Okao, M., Takano, S.-e., Aiga, Y., Yoneda, A., Hosomichi, K., & Fukami, K. (2025). Zic family member 5 promotes RIO kinase 3 expression to enhance pancreatic cancer survival. *The FEBS Journal*. URL: https://www.semanticscholar.org/paper/58cbdd638d103d33d0bdf91dfe1f7a622216ce12
[9] Babu, G., & Nobel, F. (2022). Identification of differentially expressed genes and their major pathways among the patient with COVID-19, cystic fibrosis, and chronic kidney disease. *Informatics in Medicine Unlocked*. URL: https://www.semanticscholar.org/paper/9fac26eea894a0597f8774a1bda70fef94d2db83
[10] Kimmelman, A. C., Hezel, A., Aguirre, A., Zheng, H., Paik, J., Ying, H., Chu, G. C., Zhang, J., Sahin, E., Yeo, G., Ponugoti, A. H., Nabioullin, R., DeRoo, S. C., Yang, S., Wang, X., Mcgrath, J., Protopopova, M., Ivanova, E., Zhang, J., Feng, B., Tsao, M., Redston, M., Protopopov, A., Xiao, Y., Futreal, P. A., Hahn, W., Klimstra, D., Chin, L., & DePinho, R. (2008). Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. *Proceedings of the National Academy of Sciences of the United States of America*. URL: https://www.semanticscholar.org/paper/2693422438bc3e76f2a0e8c7d8278d7097a3bc0f
[11] Du, M., Zhou, X., Fu, X., Zhang, Y., Zhang, S., Michal, J., Wang, H., & Jiang, Z. (2019). 341 Up-regulation of wound healing pathway may trigger adipogenic potentials of intramuscular progenitor cells in Wagyu as compared to Angus cattle. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/1b26770a12f6ba032bbd9dc52774e54ce5523fe1
[12] Wang, W., Yang, Y., Duan, Y., Zhao, H., & Hu, X. (2016). Limb-Bud and Heart (LBH), Target of Mir-191, Is a Novel Positive Regulator of Erythroid Differentiation. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/eb5063a7bd7a8486135d560b49b73563fe673031
[13] Das, T., Hassan, S., Feng, Q., Gretch, D., Reyes, J., & Perkins, J. (2014). RIO Kinase 3 over Expression Promotes Hepatocellular Carcinoma Invasion through Induction of Epithelial- Mesenchymal Transition and a Potential Link to WNT/β-Catenin Pathway Activation. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/58bc14a4a884ead0c7b54130ed5217b8c2a8ca27
[14] Larrayoz, M., Blakemore, S., Dobson, R., Rose-Zerilli, M., Walewska, R., Blunt, M. D., Yoshida, M., Oscier, D., Cragg, M., Steele, A., & Strefford, J. (2014). Splicing Inhibition By Spliceostatin_A Is a Promising Therapeutic Strategy in Chronic Lymphocytic Leukaemia. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/b34409cdeaf1a94d18ab2b5d6041badbfc078852
[15] Chapman, J. (2011). Molecular genetics of developmental dyslexia. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/c34d3ca4b50321ae9add2b1ea1e13143b52b8382
[16] Mishra, D., Chen, Z., Wu, Y., & Vadgama, J. (2007). Analysis of differential methylation pattern between normal prostate cells, prostate cancer cells, and between androgen dependent and independent prostate cancer cells. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/7280eab11a4698ec1e60fdb2bc42cd01876fe45c
[17] Li, Q., Xie, L., Pan, J., He, Y., Wang, E., Wu, H.-n., Xiao, J., & Feng, H. (2023). Black carp RIOK3 suppresses MDA5-mediated IFN signaling in the antiviral innate immunity. *Developmental and Comparative Immunology*. URL: https://www.semanticscholar.org/paper/9112c2d24819ac018b3051bc254cb0d606674b3b
[18] Li, J., Zhu, P., Shi, Z., Wen, L., Orkin, S. H., & Xie, H. (2024). Polycomb Repressive Complex 2 Regulates Differentiation-Stage-Specific Autophagy Gene Expression and Safeguards Normal Erythropoiesis. *Blood*. URL: https://www.semanticscholar.org/paper/705380cb429d3de9060793fdffb7683ee86989cc
[19] Singleton, D., Rouhi, P., Zois, C., Ha