TBK1 — TANK Binding Kinase 1

TBK1 — TANK Binding Kinase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TBK1 — TANK Binding Kinase 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TBK1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>TANK Binding Kinase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>12q14.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/29110" target="_blank">29110</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183735" target="_blank">ENSG00000183735</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/604834" target="_blank">604834</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UHD2" target="_blank">Q9UHD2</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[ALS](/diseases/als), [FTD](/diseases/ftd)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Motor cortex, Spinal cord, Immune cells</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Loss-of-function mutations<br>E696K<br>I397T<br>R357X</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#e

TBK1 — TANK Binding Kinase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TBK1 — TANK Binding Kinase 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TBK1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>TANK Binding Kinase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>12q14.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/29110" target="_blank">29110</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183735" target="_blank">ENSG00000183735</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/604834" target="_blank">604834</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UHD2" target="_blank">Q9UHD2</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[ALS](/diseases/als), [FTD](/diseases/ftd)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Motor cortex, Spinal cord, Immune cells</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Loss-of-function mutations<br>E696K<br>I397T<br>R357X</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">763 edges</a></td>
</tr>
</table>

TBK1 — TANK Binding Kinase 1

Pathway Diagram

Brain Atlas Resources

• [Allen Human Brain Atlas search: TBK1](https://human.brain-map.org/search?searchText=TBK1)
• [Allen Mouse Brain Atlas search: TBK1](https://mouse.brain-map.org/search/index.html?query=TBK1)
• [Allen Brain Map portal search: TBK1](https://portal.brain-map.org/search?query=TBK1)
• [BrainSpan developmental transcriptome search: TBK1](https://www.brainspan.org/search/index.html?search=TBK1)

Introduction

Tbk1 — Tank Binding Kinase 1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

TBK1 (TANK Binding Kinase 1) is a serine/threonine kinase gene located on chromosome 12q14.2 that encodes a key enzyme at the crossroads of innate immunity and selective autophagy. Dominant loss-of-function mutations in TBK1 were identified as a significant genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in 2015 through independent studies ([Cirulli et al., 2015](https://doi.org/10.1126/science.aaa3650); [Freischmidt et al., 2015](https://doi.org/10.1038/nn.4000)). TBK1 mutations represent the third most frequent genetic cause of FTD in some populations (after C9orf72 and GRN), and the second most common cause of familial ALS after C9orf72 ([Gijselinck et al., 2015](https://doi.org/10.1212/WNL.0000000000002220)). The gene is catalogued as NCBI Gene ID [29110](https://www.ncbi.nlm.nih.gov/gene/29110) and OMIM [604834](https://omim.org/entry/604834).

Function

TBK1 belongs to the IκB kinase (IKK) subfamily of kinases, originally characterized for its role in activating innate immune signaling through the induction of type I interferons in response to viral infection. The protein contains a kinase domain (KD), a ubiquitin-like domain (ULD), and a scaffold/dimerization domain (SDD) ([Ahmad et al., 2016](https://doi.org/10.1126/scisignal.aaf2155)).

Selective Autophagy

TBK1 plays a critical role in selective autophagy—the targeted degradation of damaged organelles and protein aggregates. TBK1 phosphorylates autophagy receptors optineurin (OPTN), p62/SQSTM1, NDP52 (CALCOCO2), and TAX1BP1, which bridge ubiquitinated cargo to autophagic membranes ([Richter et al., 2016](https://doi.org/10.1073/pnas.1523926113)). Specifically:

• OPTN phosphorylation at Ser473 within the UBAN domain expands OPTN's capacity to bind diverse ubiquitin chains, creating a signal amplification loop for efficient cargo recruitment ([Richter et al., 2016](https://doi.org/10.1073/pnas.1523926113)).
• p62/SQSTM1 phosphorylation at Ser403 enhances ubiquitin binding and promotes autophagosomal engulfment of polyubiquitinated mitochondria ([Matsumoto et al., 2015](https://doi.org/10.1093/hmg/ddv179)).

Innate Immune Signaling

TBK1 is a critical inducer of type I interferons, activated downstream of pattern recognition receptors including cGAS-STING and RIG-I-like receptors. Notably, TBK1 activated during autophagy does not cross-activate innate immunity signaling targets, suggesting pathway-specific regulation ([Ahmad et al., 2016](https://doi.org/10.1126/scisignal.aaf2155)).

Mitophagy

In the PINK1–Parkin mitophagy pathway, TBK1 is recruited to ubiquitinated damaged mitochondria where it phosphorylates OPTN and NDP52 to promote mitophagic clearance ([Lazarou et al., 2015](https://doi.org/10.1038/nature14893)).

Brain Expression

TBK1 is expressed in the motor cortex, spinal cord, and ubiquitously in immune cells—particularly microglia, where its loss shifts cells toward an aged-like phenotype ([Bhargava et al., 2025](https://doi.org/10.1038/s41467-025-63211-w)). Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=TBK1).

Disease Associations

TBK1 mutations are linked to the following neurodegenerative conditions:

• Amyotrophic Lateral Sclerosis (ALS) — TBK1 haploinsufficiency impairs autophagy and membrane trafficking in motor neurons ([Harding et al., 2021](https://doi.org/10.1073/pnas.2025053118)).
• Frontotemporal Dementia (FTD) — Tbk1 deletion in mice reproduces behavioral and locomotor symptoms of FTD-ALS, including social recognition deficits ([Duan et al., 2019](https://doi.org/10.1371/journal.pone.0228304)).
• ALS-FTD spectrum — Many patients present with overlapping motor neuron and cognitive symptoms.

Key Mutations

| Mutation | Type | Effect |
|----------|------|--------|
| E696K | Missense | Causes autophagolysosomal dysfunction in motor neurons, progressive motor neuron disease in mouse knock-in models ([Bhatti et al., 2024](https://doi.org/10.1084/jem.20221190)) |
| I397T | Missense | Disrupts mitophagy and accumulates damaged mitochondria |
| R357X | Nonsense | Truncation causing haploinsufficiency |
| Various LOF | Frameshift/splice | Complete loss of one functional allele |

ALS-associated missense mutations in TBK1 differentially disrupt mitophagy, with some mutations inhibiting or delaying clearance of damaged organelles, leading to accumulation of dysfunctional mitochondria that may produce cytotoxic reactive oxygen species (ROS) ([Harding et al., 2021](https://doi.org/10.1073/pnas.2025053118)).

Pathogenic Mechanisms

Therapeutic Implications

TBK1-related ALS/FTD presents potential therapeutic targets:

• Autophagy enhancement: Small molecules that boost autophagic flux may compensate for TBK1 haploinsufficiency.
• TBK1 activators: Direct pharmacological activation of remaining TBK1 protein.
• Mitophagy restoration: Targeting downstream effectors to restore mitochondrial quality control.

External Links

• NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/29110](https://www.ncbi.nlm.nih.gov/gene/29110)
• Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183735](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183735)
• OMIM: [https://omim.org/entry/604834](https://omim.org/entry/604834)
• UniProt: [https://www.uniprot.org/uniprot/Q9UHD2](https://www.uniprot.org/uniprot/Q9UHD2)
• Allen Human Brain Atlas: [TBK1 expression](https://human.brain-map.org/microarray/search/show?search_term=TBK1)

See Also

• [Genes Index](/genes)
• OPTN — Optineurin
• SQSTM1 — Sequestosome 1 (p62)))
• PINK1 — PTEN Induced Kinase 1
• [C9orf72](/entities/c9orf72)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)

Pathway Diagram

The following diagram shows the key molecular relationships involving TBK1 — TANK Binding Kinase 1 discovered through SciDEX knowledge graph analysis:

Associated Diseases

• Als — associated with

• Alzheimer — associated with

• Alzheimer's disease — associated with

• Alzheimer'S Disease — associated with

• amyotrophic lateral sclerosis — implicated in

• Amyotrophic Lateral Sclerosis — associated with

• dementia — associated with

• Dementia — associated with

• frontotemporal — associated with

• frontotemporal dementia — associated with

• Frontotemporal Dementia — associated with

• FRONTOTEMPORAL DEMENTIA — causes

• frontotemporal lobar degeneration — causes

• Parkinson — associated with