TOLLIP — Toll-Interacting Protein

TOLLIP — Toll-Interacting Protein

<div class="infobox infobox-gene">

| | |
|---|---|
| Gene Symbol | TOLLIP |
| Full Name | Toll-Interacting Protein |
| Aliases | IL-1RAcPIP |
| Chromosome | 11p15.5 |
| NCBI Gene ID | [54472](https://www.ncbi.nlm.nih.gov/gene/54472) |
| OMIM | [606277](https://omim.org/entry/606277) |
| Ensembl | [ENSG00000078902](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000078902) |
| UniProt | [Q9H0E2](https://www.uniprot.org/uniprot/Q9H0E2) |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), idiopathic pulmonary fibrosis |

</div>

Overview

TOLLIP — Toll-Interacting Protein

<div class="infobox infobox-gene">

| | |
|---|---|
| Gene Symbol | TOLLIP |
| Full Name | Toll-Interacting Protein |
| Aliases | IL-1RAcPIP |
| Chromosome | 11p15.5 |
| NCBI Gene ID | [54472](https://www.ncbi.nlm.nih.gov/gene/54472) |
| OMIM | [606277](https://omim.org/entry/606277) |
| Ensembl | [ENSG00000078902](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000078902) |
| UniProt | [Q9H0E2](https://www.uniprot.org/uniprot/Q9H0E2) |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), idiopathic pulmonary fibrosis |

</div>

Overview

TOLLIP encodes Toll-interacting protein, a multifunctional adaptor that negatively regulates Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling while simultaneously functioning as a selective [autophagy](/mechanisms/autophagy-lysosomal-pathway) receptor. TOLLIP bridges innate immune regulation and protein quality control, making it uniquely positioned at the intersection of neuroinflammation and proteostasis — two central pathogenic axes in neurodegeneration. Genetic variants in TOLLIP have been associated with altered susceptibility to [Alzheimer's disease](/diseases/alzheimers-disease) and [ALS](/diseases/amyotrophic-lateral-sclerosis).

Gene Structure and Regulation

TOLLIP spans approximately 52 kb on chromosome 11p15.5 and contains 6 exons. The gene is expressed from a bidirectional promoter responsive to inflammatory stimuli. Expression is upregulated by NF-kappaB signaling, creating a negative feedback loop that limits excessive innate immune activation[@burns2000]. In [microglia](/cell-types/microglia-neuroinflammation), TOLLIP expression is modulated by microglial activation states, with reduced expression in disease-associated microglia (DAM) phenotypes observed in neurodegeneration.

Function

TLR/IL-1R Signaling Inhibition

TOLLIP is a critical negative regulator of innate immune signaling. It binds and inhibits IL-1 receptor-associated kinase 1 (IRAK1), preventing its auto-phosphorylation and blocking downstream NF-kappaB and MAPK cascades. TOLLIP attenuates signaling from [TLR2](/genes/tlr2) and [TLR4](/genes/tlr4), key pattern recognition receptors that detect damage-associated molecular patterns (DAMPs) in neurodegeneration, and limits IL-1beta signaling through direct inhibition of the IL-1 receptor signaling complex[@zhang2002].

In the brain, this function is critical because [microglia](/cell-types/microglia) chronically activated by [amyloid-beta](/proteins/amyloid-beta-protein), [alpha-synuclein](/proteins/alpha-synuclein), or [tau](/proteins/tau) DAMPs require TOLLIP to prevent runaway neuroinflammation.

Selective Autophagy Receptor

TOLLIP functions as a selective [autophagy](/entities/autophagy) receptor independently of its immune regulatory role. The CUE (Coupling of Ubiquitin to ER degradation) domain recognizes K48- and K63-linked polyubiquitin chains on protein aggregates. TOLLIP contains a functional LIR (LC3-interacting region) motif that recruits autophagosomes to ubiquitinated cargo. It mediates aggrephagy — clearance of polyglutamine-expanded [huntingtin](/proteins/huntingtin) aggregates and other inclusion bodies — and facilitates sorting of ubiquitinated cargo into intraluminal vesicles of multivesicular bodies[@lu2014].

Endosomal Trafficking

TOLLIP regulates endosomal trafficking through its interaction with Tom1 (target of Myb1), ubiquitin, and phosphatidylinositol-3-phosphate (PI3P). The C2 domain binds PI3P-enriched endosomal membranes, positioning TOLLIP to sort ubiquitinated receptors for lysosomal degradation[@brissoni2006].

Disease Associations

Alzheimer's Disease

TOLLIP variants (rs3750920, rs5743899) have been associated with altered AD susceptibility. TOLLIP deficiency in AD models leads to exacerbated neuroinflammation (loss of TLR/IL-1R negative regulation in response to [amyloid-beta](/proteins/amyloid-beta) DAMPs), impaired aggregate clearance (reduced autophagic degradation of ubiquitinated [tau](/proteins/tau) and Abeta aggregates), and microglial dysfunction (inability to resolve inflammatory responses, shifting toward neurotoxic phenotypes)[@bhatt2017].

Amyotrophic Lateral Sclerosis

TOLLIP expression is reduced in spinal motor [neurons](/entities/neurons) of [ALS](/diseases/amyotrophic-lateral-sclerosis) patients. As a selective autophagy receptor, TOLLIP mediates clearance of ubiquitinated [TDP-43](/proteins/tdp-43-protein) and [SOD1](/proteins/sod1-protein) aggregates. Its depletion impairs aggregate clearance and promotes motor neuron degeneration[@bhatt2019].

Huntington's Disease

TOLLIP participates in clearance of mutant [huntingtin](/proteins/huntingtin-protein) aggregates via aggrephagy. Overexpression of TOLLIP reduces polyglutamine inclusion body formation, while depletion exacerbates aggregation in cellular and animal models[@lu2014].

Parkinson's Disease

TOLLIP modulates [alpha-synuclein](/proteins/alpha-synuclein) aggregate clearance and regulates neuroinflammatory responses to extracellular alpha-synuclein fibrils via TLR2 signaling modulation[@kouli2019].

Expression

TOLLIP is broadly expressed with brain-relevant patterns: [microglia](/cell-types/microglia) show the highest brain expression (essential for immune homeostasis), [astrocytes](/cell-types/astrocytes) show moderate expression (TLR signaling regulation), neurons show lower expression (primarily autophagy function), and [oligodendrocytes](/cell-types/oligodendrocytes) are also expressed (function in myelin quality control).

Allen Human Brain Atlas: [TOLLIP expression](https://human.brain-map.org/microarray/search/show?search_term=TOLLIP)

Therapeutic Relevance

Therapeutic strategies targeting TOLLIP include TOLLIP-mimetic peptides designed to enhance IRAK1 inhibition and reduce neuroinflammation, autophagy enhancement strategies to upregulate TOLLIP-mediated aggrephagy for aggregate clearance, AAV-TOLLIP gene therapy to enhance microglial anti-inflammatory capacity, and dual-target approaches exploiting TOLLIP's unique dual role in inflammation and autophagy.

See Also

• [SQSTM1](/genes/sqstm1) — p62, another selective autophagy receptor
• [RUBCN](/genes/rubcn) — Rubicon, autophagy negative regulator
• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
• [Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway)

External Links

• [NCBI Gene: TOLLIP](https://www.ncbi.nlm.nih.gov/gene/54472)
• [UniProt: Q9H0E2](https://www.uniprot.org/uniprot/Q9H0E2)
• [OMIM: 606277](https://omim.org/entry/606277)
• [GeneCards: TOLLIP](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TOLLIP)

Brain Atlas Resources

Allen Brain Atlas

• [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=TOLLIP) - Gene expression data
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/) - Mouse brain gene expression
• [BrainSpan Atlas](https://www.brainspan.org/) - Developmental transcriptome data

Related Resources

• [Allen Cell Type Atlas](https://celltypes.brain-map.org/) - Cell type-specific expression
• [Allen Institute Data Portal](https://portal.brain-map.org/) - Neuroscience data resources

References

Pathway Diagram

The following diagram shows the key molecular relationships involving TOLLIP — Toll-Interacting Protein discovered through SciDEX knowledge graph analysis: