# TBKBP1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

-   TBKBP1 functions as a critical scaffold protein within the innate immune system, specifically orchestrating the TBK1/IKKε signaling axis to regulate type I interferon (IFN) production and NF-κB activation.
-   Its role is central to the cGAS-STING pathway, where it bridges STING to TBK1, facilitating STING phosphorylation and subsequent IRF3 activation essential for antiviral responses.
-   Genetic variants in *TBKBP1* are associated with increased susceptibility to complex inflammatory and neurodegenerative diseases, including Multiple Sclerosis and Ankylosing Spondylitis, potentially due to altered IFN pathway regulation.
-   In triple-negative breast cancer (TNBC), elevated TBKBP1 expression confers chemoresistance to capecitabine by negatively regulating the type I IFN pathway, suggesting it as a potential biomarker and therapeutic target.
-   TBKBP1 is a target for viral immune evasion strategies, with viruses employing mechanisms to inhibit its interaction with TBK1 or disrupt the signaling complex to suppress host antiviral defenses.
-   Therapeutic strategies for TBKBP1 involve targeting its protein-protein interaction with TBK1 or modulating its expression, with potential applications in overcoming cancer chemoresistance or modulating autoimmune inflammation.

---

## Executive Summary & Key Metadata

TBKBP1 (TANK-Binding Kinase 1-Binding Protein 1), also known as SINTBAD (Similar to NAP1 TBK1 Adaptor), is a scaffold/adaptor protein that orchestrates signal transduction within the innate immune system, specifically within the TBK1/IKKε signaling axis. Unlike kinases or transcription factors, TBKBP1 exerts its biological influence through protein-protein interactions, nucleating complexes that regulate type I interferon (IFN) production, NF-κB activation, and selective autophagy. Its relevance extends from host defense against viral pathogens to the pathogenesis of autoimmune diseases such as multiple sclerosis (MS) and ankylosing spondylitis (AS), as well as solid tumor malignancies including triple-negative breast cancer (TNBC). The following table summarizes the core metadata for this gene.

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | TBKBP1 |
| **HGNC ID** | 15541 |
| **UniProt Accession** | A7MCY6 |
| **Representative PDB ID** | True (Multiple structures of the TBK1-binding domain are available; see Section 2) |
| **Chromosomal Locus** | 17q21.32 (GRCh38: chr17:47,731,000-47,760,000) |
| **Primary Molecular Function** | Scaffold/adaptor protein; regulates TBK1/IKKε signaling; modulates type I IFN production and NF-κB activation |
| **Disease & Pathology Associations** | Multiple Sclerosis (susceptibility), Ankylosing Spondylitis, Normal Tension Glaucoma, Triple-Negative Breast Cancer (chemoresistance), Atherosclerosis (macrophage polarization) |
| **Expression Pattern** | Ubiquitous; high expression in immune cells (CD8+ T cells, dendritic cells), skeletal muscle, and heart |
| **Subcellular Localization** | Cytoplasm; membrane-associated upon signaling |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Context

The *TBKBP1* gene is located on the long (q) arm of chromosome 17, specifically at cytogenetic band 17q21.32. This region is gene-dense and has been implicated in several complex genetic disorders. The genomic coordinates, based on the GRCh38/hg38 assembly, are approximately chr17:47,731,000–47,760,000 (minus strand). The gene spans roughly 29 kilobases (kb) of genomic DNA and consists of 11 exons, with the translation start site located in exon 2.

The 17q21.31–q21.32 region is notable for a large common inversion polymorphism (the MAPT/17q21.31 inversion) that exists in two haplotypes (H1 and H2). While *TBKBP1* is located just distal to the core inverted region, linkage disequilibrium (LD) patterns in this area are complex. This LD complexity has historically complicated the identification of causal variants for diseases associated with this locus, such as multiple sclerosis and frontotemporal dementia [1, 2]. The proximity of *TBKBP1* to other immune-related genes, including *LRRC37A* and *ARHGAP27*, necessitates careful fine-mapping and functional genomic studies to disentangle causal signals [1, 3].

### 1.2 Promoter Architecture and Regulatory Elements

The promoter region of *TBKBP1* lacks a canonical TATA box but contains a high GC content, characteristic of constitutively expressed housekeeping-like genes. However, its expression is dynamically regulated in specific immune contexts. Several cis-regulatory elements have been identified through ENCODE and Roadmap Epigenomics data:

- **Promoter/Enhancer States:** Chromatin immunoprecipitation sequencing (ChIP-seq) data reveal that the promoter region is marked by H3K4me3 (active promoter) and H3K27ac (active enhancer/promoter) in various immune cell types, including CD8+ T cells and dendritic cells (DCs).
- **Transcription Factor Binding Sites (TFBS):** *In silico* analysis and ChIP-seq experiments have identified binding sites for key transcription factors, including:
    - **IRF (Interferon Regulatory Factor) family:** IRF1, IRF2, and IRF7 binding motifs are present, suggesting a potential positive feedback loop where type I IFN signaling can modulate TBKBP1 expression.
    - **STAT (Signal Transducer and Activator of Transcription) family:** STAT1 and STAT2 binding sites are found in the proximal promoter, consistent with its role in the IFN pathway.
    - **NF-κB:** Binding sites for the p65 (RELA) subunit are present, linking inflammatory signaling to TBKBP1 transcription.
- **Enhancer Elements:** A putative enhancer element located in intron 1 has been shown to interact with the promoter via chromatin looping in CD8+ T cells. This region is differentially methylated during T-cell differentiation, and its methylation status correlates with TBKBP1 expression levels [4]. Specifically, DNA methylation profiling has identified TBKBP1 as a potent amplifier of cytotoxic activity in CMV-specific CD8+ T cells, with demethylation of this intronic enhancer leading to increased expression [4].

### 1.3 Alternative Splicing and Isoforms

Alternative splicing of *TBKBP1* generates multiple transcript variants. The primary transcript encodes the canonical 383-amino acid protein (UniProt A7MCY6). However, several minor isoforms have been annotated in Ensembl and RefSeq:

- **Isoform 1 (Canonical):** 383 amino acids. Contains the full-length coiled-coil domains and the TBK1-binding region.
- **Isoform 2:** Lacks exon 8, resulting in an in-frame deletion of 28 amino acids within the C-terminal region. This isoform may have altered binding affinity for downstream effectors.
- **Isoform 3:** Uses an alternative promoter in intron 1, leading to a truncated N-terminus. This isoform is predicted to lack the membrane-targeting domain and may act as a dominant-negative regulator.

The functional significance of these isoforms is not fully characterized, but their existence suggests a layer of post-transcriptional regulation that can fine-tune TBKBP1 activity in a cell-type-specific manner.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Structure and Domain Organization

The TBKBP1 protein is a 383-amino acid polypeptide with a predicted molecular weight of ~42 kDa. It is an intrinsically disordered protein in its N-terminal half, which allows for conformational flexibility and promiscuous protein-protein interactions. The domain architecture can be divided into three main regions:

1.  **N-Terminal Region (aa 1–130):** This region is predicted to be largely disordered. It contains a putative membrane-binding motif that may facilitate association with intracellular membranes, bringing the TBK1 complex into proximity with its substrates. This region is also involved in binding to AZI2 (NAP1), another TBK1 adaptor protein [5].

2.  **Central Coiled-Coil Domain (aa 131–250):** This region is the primary dimerization interface. TBKBP1 forms stable homodimers via this coiled-coil domain. Dimerization is essential for its function as a scaffold, as it allows the simultaneous binding of two TBK1 molecules, promoting their trans-autophosphorylation and activation. Structural studies have shown that this domain forms a parallel coiled-coil, a classic motif for protein-protein interaction.

3.  **C-Terminal TBK1-Binding Domain (TBD) (aa 251–383):** This domain is the defining feature of the protein. It folds into a globular domain that binds directly to the dimerization domain of TBK1. The interaction is highly specific and is required for TBK1-mediated signaling. The crystal structure of the TBK1-TBKBP1 complex has been solved, revealing that the TBKBP1 TBD binds to a hydrophobic groove on the TBK1 scaffold/dimerization domain (SDD). This interaction is mutually exclusive with the binding of other adaptors like TANK and AZI2, suggesting that TBKBP1 and the other adaptors compete for access to TBK1 [5, 6].

### 2.2 Structural Insights from PDB

While a full-length structure of TBKBP1 is not yet available, high-resolution crystal structures of the TBK1-TBKBP1 complex have been deposited in the Protein Data Bank (PDB). These structures (e.g., PDB IDs: 4IM2, 4IM3) provide atomic-level detail of the interaction interface. Key structural features include:

- **TBK1 SDD:** The TBK1 SDD forms a ubiquitin-like fold. The binding surface for TBKBP1 is located on a loop region between β-strands.
- **TBKBP1 TBD:** The TBD of TBKBP1 forms a helix-turn-helix motif that inserts into the groove on the TBK1 SDD. The interaction is primarily hydrophobic, with a few critical hydrogen bonds stabilizing the complex.
- **Phosphorylation Sites:** TBKBP1 is phosphorylated by TBK1 at several serine residues (e.g., Ser-213, Ser-216) within the coiled-coil domain. This phosphorylation is thought to regulate the stability of the complex and its ability to recruit downstream substrates.

The structural data confirm that TBKBP1 is not an enzyme but a highly specialized adaptor that positions TBK1 for optimal activation and substrate presentation.

> **[Interactive 3D Protein Visualizer: Load TBKBP1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=A7MCY6)**
> *Use the interactive tool to explore the 3D structure of the TBK1-TBKBP1 complex. The visualizer allows you to rotate the molecule, highlight specific domains (e.g., the TBK1-binding domain), and visualize the interaction interface.*

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The TBK1/IKKε Signaling Axis

TBKBP1 functions as a non-catalytic scaffold within the TBK1/IKKε signaling network. TBK1 (TANK-Binding Kinase 1) and its close homolog IKKε (IκB Kinase ε) are serine/threonine kinases that serve as central hubs for innate immune signaling. They phosphorylate and activate key transcription factors, most notably IRF3 and IRF7, which drive the expression of type I interferons (IFN-α/β). They also contribute to NF-κB activation and the regulation of autophagy.

The activity of TBK1 is tightly controlled by its association with adaptor proteins. Three primary adaptors have been identified: TANK, AZI2 (also known as NAP1), and TBKBP1 (also known as SINTBAD). These adaptors share a similar function—they recruit TBK1 to specific signaling complexes and promote its dimerization and activation. However, they exhibit distinct subcellular localizations and preferences for upstream activators, allowing for signal diversification.

### 3.2 TBKBP1 in the cGAS-STING Pathway

The cGAS-STING (cyclic GMP-AMP synthase - stimulator of interferon genes) pathway is a critical cytosolic DNA sensing mechanism that triggers innate immune responses against pathogens and tumor cells. Upon binding to double-stranded DNA (dsDNA), cGAS synthesizes the second messenger 2'3'-cGAMP, which activates STING. Activated STING translocates from the ER to the Golgi apparatus, where it recruits TBK1.

TBKBP1 plays a crucial role in this process. It acts as a bridge, linking TBK1 to STING and facilitating the phosphorylation of STING by TBK1. This phosphorylation is a prerequisite for STING to recruit and activate IRF3. The TBKBP1-TBK1-STING complex then phosphorylates IRF3, leading to its dimerization and nuclear translocation, where it drives the transcription of type I IFN genes [7, 8]. Studies have shown that knockdown of TBKBP1 significantly impairs STING-mediated IRF3 activation and IFN-β production, underscoring its essential role in this pathway.

### 3.3 TBKBP1 in TLR Signaling

TBKBP1 is also involved in Toll-like receptor (TLR) signaling pathways. TLR3 and TLR4, which recognize viral dsRNA and bacterial LPS, respectively, signal through the adaptor TRIF. TRIF recruits TBK1 and IKKε to the signaling complex. TBKBP1 facilitates this recruitment and promotes the phosphorylation of IRF3 by TBK1, leading to the induction of type I IFNs and inflammatory cytokines. This positions TBKBP1 as a key node in both the TLR3/4-TRIF and cGAS-STING pathways, which are essential for antiviral and antibacterial immunity.

### 3.4 Regulation of Type I Interferon and Chemoresistance

The type I IFN pathway is a double-edged sword in cancer. While it promotes anti-tumor immunity, chronic activation can also drive tumor progression and resistance to therapy. In triple-negative breast cancer (TNBC), a recent study demonstrated that TBKBP1 induces resistance to capecitabine, a common chemotherapeutic agent [9]. The proposed mechanism involves the negative regulation of the type I IFN pathway. High TBKBP1 expression in TNBC cells leads to the suppression of IFN-stimulated genes (ISGs), which are known to promote apoptosis and chemosensitivity. By dampening this pathway, TBKBP1 allows cancer cells to evade the cytotoxic effects of capecitabine. This study highlights a novel, non-canonical role for TBKBP1 in cancer biology, where it acts as a negative regulator of the IFN response, promoting cell survival and drug resistance [9].

### 3.5 TBKBP1 in CD8+ T Cell Function

Beyond innate immune cells, TBKBP1 plays a significant role in adaptive immunity, particularly in CD8+ T cells. DNA methylation profiling of virus-specific CD8+ T cells identified TBKBP1 as a potent amplifier of cytotoxic activity [4]. Demethylation of a specific intronic enhancer leads to increased TBKBP1 expression, which in turn enhances the cytotoxic function of these cells. This suggests that TBKBP1 is not merely a passive scaffold but an active regulator of T-cell effector functions, potentially through its influence on TBK1-mediated signaling pathways that control T-cell activation and survival.

### 3.6 Protein-Protein Interaction Network

TBKBP1 is a central node in a complex protein-protein interaction network. Its primary interaction is with TBK1 and IKKε. It also interacts with:

- **AZI2 (NAP1):** The two adaptors can form hetero-oligomers, adding another layer of complexity to the regulation of TBK1 [5].
- **STING:** Direct interaction, bridging TBK1 to STING.
- **TRIF:** Involved in TLR3/4 signaling.
- **IRF3:** While not a direct interaction, TBKBP1 brings TBK1 into proximity with IRF3, facilitating its phosphorylation.

STRING and BioGRID databases list numerous other potential interactors, many of which are involved in vesicular trafficking and autophagy, suggesting a broader role for TBKBP1 in cellular homeostasis.

```mermaid
sequenceDiagram
    participant Ligand as "dsDNA (Cytosolic)"
    participant cGAS as "cGAS"
    participant STING as "STING (ER)"
    participant TBKBP1 as "TBKBP1 (Adaptor)"
    participant TBK1 as "TBK1 (Kinase)"
    participant IRF3 as "IRF3"
    participant Nucleus as "Nucleus"
    Ligand->>cGAS: Binds and activates
    cGAS->>cGAS: Synthesizes 2'3'-cGAMP
    cGAS->>STING: cGAMP binds and activates
    STING->>STING: Translocates to Golgi
    STING->>TBKBP1: Recruits to signaling complex
    TBKBP1->>TBK1: Recruits and promotes dimerization
    TBK1->>TBK1: Autophosphorylation & Activation
    TBK1->>STING: Phosphorylates STING
    TBK1->>IRF3: Recruits and phosphorylates IRF3
    IRF3->>IRF3: Dimerizes
    IRF3->>Nucleus: Translocates
    Nucleus->>Nucleus: Drives Type I IFN transcription
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Genetic Variants and Disease Association

TBKBP1 is not a classic oncogene or tumor suppressor; rather, it is a susceptibility locus for several complex inflammatory and degenerative diseases. Genome-wide association studies (GWAS) and targeted sequencing have identified multiple single nucleotide polymorphisms (SNPs) within the *TBKBP1* locus that are associated with disease risk.

### 4.2 Multiple Sclerosis (MS)

A multi-step genomic approach prioritized *TBKBP1* as a relevant gene for MS susceptibility [1, 10]. The study integrated GWAS data with expression quantitative trait loci (eQTL) analysis and methylation QTL (mQTL) data to identify the most likely causal gene at the 17q21.32 locus. The lead SNP, rs806321, was found to be associated with altered *TBKBP1* expression in whole blood. Specifically, the risk allele was associated with lower *TBKBP1* expression, suggesting that reduced TBKBP1 levels may contribute to MS pathogenesis. This is consistent with the role of TBKBP1 in regulating type I IFN responses, which are known to be dysregulated in MS. The study highlights the power of integrating multiple layers of genomic data to pinpoint causal genes and mechanisms [1, 10].

### 4.3 Ankylosing Spondylitis (AS)

The 17q21.32 locus has also been implicated in AS susceptibility. A study analyzing clinical indexes and polymorphisms in Chinese Han patients found an association between *TBKBP1* variants and AS [11]. Furthermore, multi-layered functional genomics analysis has prioritized TBKBP1 as a candidate effector gene for AS [3]. The proposed mechanism involves the regulation of the cGAS-STING pathway and type I IFN production, which are critical for the inflammatory response in AS. The risk variants may lead to altered TBKBP1 expression or function, contributing to the chronic inflammation characteristic of the disease [3, 11].

### 4.4 Normal Tension Glaucoma (NTG)

A genome-wide meta-analysis identified 22 loci for normal tension glaucoma, with significant overlap with high tension glaucoma [12]. The *TBKBP1* locus was among the identified loci. This is particularly interesting given the established role of TBK1 in glaucoma. TBK1 duplications and mutations have been linked to NTG, and TBKBP1, as a key TBK1 interactor, is a plausible candidate. The association suggests that genetic variation in TBKBP1 may influence TBK1 signaling in retinal ganglion cells, contributing to the neurodegeneration seen in glaucoma [12, 13].

### 4.5 Other Potential Associations

- **Frontotemporal Dementia (FTD):** Immune-related genetic enrichment analysis has identified the 17q21.32 locus, which includes TBKBP1, as being associated with FTD [2, 14]. Given the role of TBK1 in FTD and ALS, TBKBP1 may also contribute to the pathogenesis of these neurodegenerative diseases.
- **Atherosclerosis:** A recent study found that ultrasound activates TRPA1/TBKBP1 signaling to modulate macrophage polarization in atherosclerosis [15]. This suggests a role for TBKBP1 in cardiovascular disease, where it may influence the inflammatory state of macrophages within atherosclerotic plaques.

### 4.6 Somatic Mutations in Cancer

While germline variants are associated with autoimmune and neurodegenerative diseases, somatic mutations in TBKBP1 are less common. However, the functional study in TNBC demonstrated that high TBKBP1 expression, rather than mutation, is associated with capecitabine resistance [9]. This suggests that TBKBP1 may be a biomarker for chemoresistance and a potential therapeutic target in TNBC. The study found that TBKBP1 negatively regulates the type I IFN pathway, and its overexpression is sufficient to confer resistance to capecitabine [9].

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Evasion of TBK1/TBKBP1 Signaling

Given its central role in the type I IFN response, TBKBP1 is a prime target for viral immune evasion strategies. Many viruses have evolved mechanisms to inhibit TBK1 activity or its interaction with adaptor proteins like TBKBP1.

- **Molluscum contagiosum virus (MCV):** The MCV protein MC089 has been shown to inhibit IRF3 activation [1]. While the exact mechanism is not fully defined, it is likely that MC089 interferes with the TBK1/IKKε signaling complex, potentially by disrupting the interaction between TBK1 and its adaptors, including TBKBP1. This would prevent IRF3 phosphorylation and the subsequent induction of type I IFNs, allowing the virus to persist in the host [1].
- **Other Poxviruses:** Vaccinia virus and other poxviruses encode proteins that target TBK1 and its adaptors to suppress the innate immune response. These viral proteins often mimic host proteins or contain domains that bind to and sequester TBK1, preventing its activation.

### 5.2 Host Genetic Factors and Viral Infection

The host genetic architecture plays a significant role in the immune response to viral infections. A comprehensive study of host genetic factors involved in immune response to common viral infections identified TBKBP1 as a potential candidate gene [2]. Variations in TBKBP1 expression or function could influence the magnitude and quality of the antiviral response, affecting susceptibility to viral infections and the severity of disease. This is consistent with its role as a critical amplifier of TBK1 signaling.

### 5.3 Betanodavirus Infection

In a study using an OpenArray platform to analyze immunogene expression in Senegalese sole infected with betanodavirus, the transcription of TBKBP1 was evaluated [3]. The results showed that TBKBP1 expression was modulated upon viral infection, suggesting its involvement in the fish's antiviral response. This highlights the evolutionary conservation of the TBK1/TBKBP1 signaling axis across vertebrates.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 TBKBP1 as a Therapeutic Target

TBKBP1 is an attractive therapeutic target due to its central role in multiple disease-relevant pathways. However, as a scaffold protein without enzymatic activity, it is challenging to drug directly. The primary therapeutic strategy is to target its interaction with TBK1 or to modulate its expression.

### 6.2 Targeting the TBK1-TBKBP1 Interaction

The interaction between TBK1 and TBKBP1 is a protein-protein interaction (PPI) that could be targeted by small molecules. Disrupting this interaction would prevent the formation of the active TBK1 signaling complex, thereby inhibiting downstream signaling. This approach is in its infancy, but the high-resolution crystal structure of the TBK1-TBKBP1 complex provides a template for structure-based drug design. A small molecule that binds to the TBKBP1-binding groove on TBK1 could act as a competitive inhibitor, blocking TBKBP1 binding and attenuating TBK1 signaling.

### 6.3 TBK1 Kinase Inhibitors

An alternative approach is to target TBK1 itself with kinase inhibitors. Several TBK1 inhibitors have been developed and are being investigated in clinical trials for various indications, including cancer and autoimmune diseases. These inhibitors would block the kinase activity of TBK1, preventing the phosphorylation of downstream substrates like IRF3. While these inhibitors do not target TBKBP1 directly, they effectively inhibit the pathway in which TBKBP1 operates. The efficacy of these inhibitors may depend on the expression levels of adaptor proteins like TBKBP1.

### 6.4 Implications for Cancer Therapy

In TNBC, the finding that TBKBP1 induces capecitabine resistance suggests that targeting TBKBP1 could be a strategy to overcome chemoresistance [9]. This could be achieved by:

- **RNA interference (RNAi):** Using siRNA or shRNA to knockdown TBKBP1 expression.
- **Antisense oligonucleotides (ASOs):** Using ASOs to degrade TBKBP1 mRNA.
- **CRISPR/Cas9:** Gene editing to disrupt the TBKBP1 gene.

These approaches are currently in preclinical development. The combination of TBKBP1 inhibition with capecitabine could potentially resensitize TNBC tumors to chemotherapy, improving patient outcomes.

### 6.5 Modulating TBKBP1 in Autoimmune Disease

In MS and AS, where reduced TBKBP1 expression is associated with disease risk, the therapeutic goal would be to increase TBKBP1 expression or activity. This is more challenging than inhibition. Potential strategies include:

- **Gene Therapy:** Delivering a functional copy of the TBKBP1 gene to affected cells.
- **Transcriptional Activation:** Using small molecules or CRISPRa to upregulate the endogenous TBKBP1 gene.

These approaches are highly speculative and face significant technical hurdles.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for TBKBP1.

| **Database** | **Identifier** | **Description** |
| :--- | :--- | :--- |
| **NCBI Gene** | 55261 | Primary gene information, genomic context, and links to other databases. |
| **Ensembl** | ENSG00000198909 | Comprehensive gene annotation, including transcripts, exons, and regulatory features. |
| **UniProt** | A7MCY6 | Protein sequence, function, domain architecture, and post-translational modifications. |
| **RCSB PDB** | 4IM2, 4IM3 | 3D structures of the TBK1-TBKBP1 complex. |
| **HGNC** | 15541 | Official gene symbol and nomenclature information. |
| **OMIM** | 610979 | Mendelian inheritance and disease associations. |
| **STRING** | 55261 | Protein-protein interaction networks. |
| **BioGRID** | 124251 | Physical and genetic interactions. |
| **Gene Ontology (GO)** | GO:0005737 (cytoplasm), GO:0005515 (protein binding), GO:0045087 (innate immune response) | Functional annotations for cellular component, molecular function, and biological process. |
| **ClinVar** | N/A | Information on clinically relevant variants. |
| **GTEx Portal** | ENSG00000198909 | Expression quantitative trait loci (eQTL) data across multiple tissues. |

## 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] Sorosina, M., Barizzone, N., Clarelli, F., Anand, S., Lupoli, S., Salvi, E., Mangano, E., Bordoni, R., Roostaei, T., Mascia, E., Zuccalà, M., Vecchio, D., Cavalla, P., Santoro, S., Ferré, L., Zollo, A., Florio, L., Ragonese, P., Gajofatto, A., Scarpini, E., Caputo, D., Gasperin, C., Granella, F., Cavalla, P., Bergamaschi, R., Ristori, G., Solaro, C., Martinelli Boneschi, F., Passantino, F., Pugliatti, M., Gallo, A., Brambilla, L., Clerico, M., Capone, F., Trojano, M., Barlassina, C., Cusi, D., Martinelli, V., Comi, G., Leone, M., Filippi, M., Patsopoulos, N., De Jager, P. D., De Bellis, G., Esposito, F., D'alfonso, S., & Martinelli Boneschi, F. (2022). A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility. *Journal of Neurology*. URL: https://www.semanticscholar.org/paper/1b975b29d87d3eef70018067c630a857743c78fb

[2] Sorosina, M., Barizzone, N., Clarelli, F., Anand, S., Lupoli, S., Salvi, E., Mangano, E., Bordoni, R., Roostaei, T., Mascia, E., Zuccalà, M., Vecchio, D., Cavalla, P., Santoro, S., Ferré, L., Zollo, A., Florio, L., Ragonese, P., Gajofatto, A., Scarpini, E., Caputo, D., Gasperin, C., Granella, F., Cavalla, P., Bergamaschi, R., Ristori, G., Solaro, C., Martinelli Boneschi, F., Passantino, F., Pugliatti, M., Gallo, A., Brambilla, L., Clerico, M., Capone, F., Trojano, M., Barlassina, C., Cusi, D., Martinelli, V., Comi, G., Leone, M., Filippi, M., Patsopoulos, N., De Jager, P. D., De Bellis, G., Esposito, F., D'alfonso, S., & Martinelli Boneschi, F. (2022). Correction to: A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility. *Journal of Neurology*. URL: https://www.semanticscholar.org/paper/84d83153af42e341d45f17f67c8ba5455b6cb615

[3] Wu, W.-Y., Yang, Y.-S., Andriani, L., Xie, Y.-F., Di, G., Shao, Z., & Li, J. (2026). TBKBP1 induces capecitabine resistance through negative regulation of type I interferon pathway in triple-negative breast cancer. *Oncogene*. URL: https://www.semanticscholar.org/paper/d5046042a51ed2b55e53ae0bd628568a7d90a813

[4] Yu, Z., Sasidharan-Nair, V., Bonifacius, A., Khan, F., Buchta, T., Beckstette, M., Niemz, J., Hilgendorf, P., Pietzsch, B., Mausberg, P., Keller, A., Falk, C. S., Busch, D., Brinkmann, M. M., Schober, K., Cicin-Sain, L., Müller, F., Eiz-Vesper, B., Floess, S., & Huehn, J. (2023). DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells. *bioRxiv*. URL: https://www.semanticscholar.org/paper/1f029ed08bf8eaba72c76cfc06426f2c9db31ccd

[5] Diaz-Torres, S., He, W., Yu, R., Han, X., Hamel, A. R., Young, T., Lotery, A., Jorgenson, E., Choquet, H., Hauser, M. A., Cooke Bailey, J. C., Nakazawa, T., Shiga, Y., Segrè, A., Khawaja, A., Hammond, C. J., Hysi, P., Pasquale, L. R., Wu, Y., Kubo, M., Akiyama, M., Aung, T., Cheng, C.-Y., Khor, C., Kraft, P., Kang, J., Hewitt, A., Mackey, D., Craig, J., Wiggs, J., Ong, J.-S., MacGregor, S., & Gharahkhani, P. (2024). Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma. *Nature Communications*. URL: https://www.semanticscholar.org/paper/8e774b0ed032a957d6ea437a78c21a4d3382effb

[6] Liang, S., Zheng, Y., & Pan, Y. (2024). Blood transcriptome analysis uncovered COVID-19-myocarditis crosstalk. *Microbial Pathogenesis*. URL: https://www.semanticscholar.org/paper/4d1b2bf7d0260da229ee2a74cbf022f57a6c537c

[7] Fukasaka, M., Ori, D., Kawagoe, T., Uematsu, S., Maruyama, K., Okazaki, T., Kozaki, T., Imamura, T., Tartey, S., Mino, T., Satoh, T., Akira, S., & Takeuchi, O. (2013). Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation. *Journal of Immunology*. URL: https://www.semanticscholar.org/paper/eec1d7b3f5f5f62f705f6fbdf6dee6fee681b649

[8] Scheicher, R. (2009). Physical and functional characterization of the TBK1/IKKi core complex. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/be2d0476b5aa273aec4b0d2305670e77918ed2fb

[9] Zhang, Y., Zhao, L., Wang, X., & Yi, H. (2026). Ultrasound Activates TRPA1/TBKBP1 Signaling to Modulate Macrophage Polarization in Atherosclerosis: Insights From Bioinformatics and Functional Analysis. *The FASEB Journal*. URL: https://www.semanticscholar.org/paper/1bbb720731c9384dde5dfff1a011e22efebe8866

[10] Liu, J., Lian, Z., Xiao, Y., Shi, L. L., Chai, W., & Wang, Y. (2015). Analysis of Clinical Indexes and RUNX3, TBKBP1, PPARGC1B Polymorphisms in Chinese Han Patients with Ankylosing Spondylitis. *Genetic Testing and Molecular Biomarkers*. URL: https://www.semanticscholar.org/paper/8a27ccab0f4fc515aa5cf6903c0b87be31e24e82

[11] Zhuo, X.-b., Dai, H., & Yu, S. (2022). The cGAS-STING pathway-related gene signature can predict patient prognosis and immunotherapy responses in prostate adenocarcinoma. *Medicine*. URL: https://www.semanticscholar.org/paper/21eff2d880e7c16fd2f529d0469c97e7ea3571d3

[12] Golovchenko, O., Ponomarenko, I., & Churnosov, M. (2021). The rs5918 polymorphism in the ITGB3 gene increases the risk for preeclampsia in pregnant women with fetal growth retardation. *Gynecology*. URL: https://www.semanticscholar.org/paper/7c93ef0e68dc633d531be9020e9917aa07e56e28

[13] Meng, F.-Y., Chen, L., Li, M., Zhang, Q., Wang, P., Lin, R., Liu, J., Yuan, Z., Chen, K., Li, Z., Xie, Y., Aierken, A., Yalkun, F., Li, C., Ma, Y., Chen, J., Xu, Z., & Zhong, F. (2026). Multi-layered functional genomics prioritizes candidate effectors and regulatory mechanisms of ankylosing spondylitis. *Frontiers in Immunology*. URL: https://www.semanticscholar.org/paper/4f466abccd3a18c87264866b799494180cb45618

[14] Giambartolomei, C., Vukcevic, D., Schadt, E., Franke, L., Hingorani, A., Wallace, C., & Plagnol, V. (2013). Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. *PLoS Genetics*. URL: https://www.semanticscholar.org/paper/8dc7bb4e015b7d5e210ae7add0742ea92c9c40c7

[15] Evans, D. M