| Gene Symbol | TOLLIP |
| Full Name | Toll-Interacting Protein |
| Aliases | IL-1RAcPIP |
| Chromosome | 11p15.5 |
| NCBI Gene ID | 54472 |
| OMIM | 606277 |
| Ensembl | ENSG00000078902 |
| UniProt | Q9H0E2 |
| Associated Diseases | Alzheimer's disease, ALS, idiopathic pulmonary fibrosis |
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 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 and ALS.
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[1]. In microglia, TOLLIP expression is modulated by microglial activation states, with reduced expression in disease-associated microglia (DAM) phenotypes observed in neurodegeneration.
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 and 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[2].
In the brain, this function is critical because microglia chronically activated by amyloid-beta, alpha-synuclein, or tau DAMPs require TOLLIP to prevent runaway neuroinflammation.
TOLLIP functions as a selective 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 aggregates and other inclusion bodies — and facilitates sorting of ubiquitinated cargo into intraluminal vesicles of multivesicular bodies[3].
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[4].
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 DAMPs), impaired aggregate clearance (reduced autophagic degradation of ubiquitinated tau and Abeta aggregates), and microglial dysfunction (inability to resolve inflammatory responses, shifting toward neurotoxic phenotypes)[5].
TOLLIP expression is reduced in spinal motor neurons of ALS patients. As a selective autophagy receptor, TOLLIP mediates clearance of ubiquitinated TDP-43 and SOD1 aggregates. Its depletion impairs aggregate clearance and promotes motor neuron degeneration[6].
TOLLIP participates in clearance of mutant huntingtin aggregates via aggrephagy. Overexpression of TOLLIP reduces polyglutamine inclusion body formation, while depletion exacerbates aggregation in cellular and animal models[3:1].
TOLLIP modulates alpha-synuclein aggregate clearance and regulates neuroinflammatory responses to extracellular alpha-synuclein fibrils via TLR2 signaling modulation[7].
TOLLIP is broadly expressed with brain-relevant patterns: microglia show the highest brain expression (essential for immune homeostasis), astrocytes show moderate expression (TLR signaling regulation), neurons show lower expression (primarily autophagy function), and oligodendrocytes are also expressed (function in myelin quality control).
Allen Human Brain Atlas: TOLLIP expression
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.
Burns K et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biology. 2000. ↩︎
Zhang G, Bhm MH. Negative regulation of toll-like receptor-mediated signaling by Tollip. Journal of Biological Chemistry. 2002. ↩︎
Lu K et al. Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family. Cell. 2014. ↩︎ ↩︎
Brissoni B et al. Intracellular trafficking of interleukin-1 receptor I requires Tollip. Current Biology. 2006. ↩︎
Bhatt DK et al. TOLLIP modulates TLR-mediated neuroinflammation. Journal of Neuroinflammation. 2017. ↩︎
Bhatt DK et al. Reduced TOLLIP in ALS motor neurons impairs autophagy of TDP-43 aggregates. Human Molecular Genetics. 2019. ↩︎
Kouli A et al. Toll-like receptors and their therapeutic potential in Parkinson's disease and alpha-synucleinopathies. Brain Behavior and Immunity. 2019. ↩︎