TOLLIP is a multifunctional adaptor protein with dual roles in innate immune regulation and selective [autophagy](/mechanisms/autophagy-lysosomal-pathway). Originally identified as a negative regulator of Toll-like receptor (TLR) and IL-1 receptor signaling, TOLLIP is now recognized as a selective [autophagy](/entities/autophagy) receptor that targets ubiquitinated protein aggregates for autophagic degradation. This dual functionality places TOLLIP at the critical intersection of neuroinflammation and proteostasis in neurodegenerative diseases[@burns2000].
Structure
TOLLIP contains three functional domains. The N-terminal TBD (Tom1-binding domain) mediates interaction with Tom1 and Tom1L1 for endosomal trafficking. The central C2 domain binds phosphatidylinositol-3-phosphate (PI3P) on endosomal membranes and contains the LIR (LC3-interacting region) motif for autophagosome recruitment. The C-terminal CUE (Coupling of Ubiquitin to ER degradation) domain recognizes mono- and polyubiquitin chains on cargo destined for degradation[@brissoni2006].
TOLLIP is a multifunctional adaptor protein with dual roles in innate immune regulation and selective [autophagy](/mechanisms/autophagy-lysosomal-pathway). Originally identified as a negative regulator of Toll-like receptor (TLR) and IL-1 receptor signaling, TOLLIP is now recognized as a selective [autophagy](/entities/autophagy) receptor that targets ubiquitinated protein aggregates for autophagic degradation. This dual functionality places TOLLIP at the critical intersection of neuroinflammation and proteostasis in neurodegenerative diseases[@burns2000].
Structure
TOLLIP contains three functional domains. The N-terminal TBD (Tom1-binding domain) mediates interaction with Tom1 and Tom1L1 for endosomal trafficking. The central C2 domain binds phosphatidylinositol-3-phosphate (PI3P) on endosomal membranes and contains the LIR (LC3-interacting region) motif for autophagosome recruitment. The C-terminal CUE (Coupling of Ubiquitin to ER degradation) domain recognizes mono- and polyubiquitin chains on cargo destined for degradation[@brissoni2006].
The CUE domain specifically recognizes K48- and K63-linked polyubiquitin chains, enabling TOLLIP to bridge ubiquitinated aggregates to the autophagy machinery. The LIR motif (WXXL) mediates direct interaction with [LC3](/proteins/lc3-protein)/GABARAP family members on autophagosomal membranes.
Normal Function
Innate Immune Regulation
TOLLIP inhibits TLR signaling by sequestering IRAK1 in an inactive complex. Upon IL-1/TLR stimulation, TOLLIP releases IRAK1 in a phosphorylation-dependent manner, providing timed control of inflammatory signaling. In [microglia](/cell-types/microglia), this function prevents chronic inflammatory activation by damage-associated molecular patterns (DAMPs) including [amyloid-beta](/proteins/amyloid-beta-protein) and [alpha-synuclein](/proteins/alpha-synuclein)[@zhang2002].
Aggrephagy
TOLLIP serves as an autophagy receptor for ubiquitinated protein aggregates. It recognizes polyubiquitinated misfolded proteins through its CUE domain and recruits them to autophagosomes via its LIR motif. This aggrephagy pathway is critical for clearance of polyglutamine aggregates, [TDP-43](/proteins/tdp-43-protein) inclusions, and [SOD1](/proteins/sod1-protein) aggregates[@lu2014].
Endosomal Sorting
TOLLIP participates in ESCRT-independent sorting of ubiquitinated receptors into intraluminal vesicles of multivesicular bodies (MVBs), facilitating their lysosomal degradation[@brissoni2006].
Role in Disease
Neurodegeneration
TOLLIP deficiency exacerbates neurodegeneration through two parallel mechanisms: unrestrained neuroinflammation from loss of TLR/IL-1R negative regulation, and impaired aggregate clearance from loss of autophagy receptor function. In AD models, TOLLIP depletion increases microglial TNF-alpha and IL-1beta production while simultaneously reducing clearance of ubiquitinated [tau](/proteins/tau) aggregates[@bhatt2017].
In ALS, reduced TOLLIP expression in motor [neurons](/entities/neurons) impairs clearance of [TDP-43](/proteins/tdp-43-protein) cytoplasmic inclusions[@bhatt2019]. In Huntington's disease, TOLLIP overexpression reduces polyglutamine aggregation[@lu2014].
Therapeutic Targeting
Strategies include TOLLIP overexpression via gene therapy to enhance both anti-inflammatory and aggregate clearance functions simultaneously, small molecules that enhance TOLLIP-cargo interaction, and TOLLIP-mimetic peptides for aggregate-targeted autophagy.
See Also
[TOLLIP Gene](/genes/tollip)
[SQSTM1/p62](/genes/sqstm1) — related autophagy receptor
[PDB structures for TOLLIP](https://www.rcsb.org/search?q=TOLLIP)
References
[Burns K et al, Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor (2000)](https://pubmed.ncbi.nlm.nih.gov/10688888/)
[Brissoni B et al, Intracellular trafficking of interleukin-1 receptor I requires Tollip (2006)](https://pubmed.ncbi.nlm.nih.gov/16636064/)
[Zhang G, Ghosh S, Negative regulation of toll-like receptor-mediated signaling by Tollip (2002)](https://pubmed.ncbi.nlm.nih.gov/12015306/)
[Lu K et al, Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family (2014)](https://pubmed.ncbi.nlm.nih.gov/25099252/)
[Bhatt DK et al, TOLLIP modulates TLR-mediated neuroinflammation (2017)](https://pubmed.ncbi.nlm.nih.gov/28899752/)
[Bhatt DK et al, Reduced TOLLIP in ALS motor neurons impairs autophagy of TDP-43 aggregates (2019)](https://pubmed.ncbi.nlm.nih.gov/31147404/)