TOLLIP

This gene encodes a ubiquitin-binding protein that interacts with several Toll-like receptor (TLR) signaling cascade components. The encoded protein regulates inflammatory signaling and is involved in interleukin-1 receptor trafficking and in the turnover of IL1R-associated kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]
Diseases associated with TOLLIP include Lymphoproliferative Syndrome, X-Linked, 1 and Idiopathic Interstitial Pneumonia. Among its related pathways are Innate Immune System and Bacterial infections in CF airways. Gene Ontology (GO) annotations related to this gene include obsolete signal transducer activity and kinase binding.
Component of the signaling pathway of IL-1 and Toll-like receptors (PubMed:10854325, 11751856).
Inhibits cell activation by microbial products.
Recruits IRAK1 to the IL-1 receptor complex (PubMed:10854325).
Inhibits IRAK1 phosphorylation and kinase activity (PubMed:11751856).
Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates (PubMed:25042851).
The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates (PubMed:25042851).
In a complex with TOM1, recruits ubiquitin-conjugated proteins onto early endosomes (PubMed:15047686).
Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P) (PubMed:26320582).
Cytoplasm {ECO:0000269 PubMed:31263572}5
Endosome {ECO:0000269 PubMed:15047686, 31263572}
Early endosome {ECO:0000269 PubMed:15047686, 26320582}
Note: Localized to endo/exosomal vesicles {ECO:0000269 PubMed:31263572}
Quaternary structure:
Oligomerizes (PubMed:11751856).
Interacts (via C-terminus) with TLR2 and the TLR4-MD2 complex (PubMed:11751856).
Exists as complex with IRAK1 in unstimulated cells (PubMed:10854325).
Upon IL-1 signaling, binds to the activated IL-1 receptor complex containing IL-1RI, IL-1RacP and the adapter protein MyD88, where it interacts with the TIR domain of IL-1RacP (PubMed:10854325).
MyD88 then triggers IRAK1 autophosphorylation, which in turn leads to the dissociation of IRAK1 from TOLLIP and IL-1RAcP (PubMed:10854325).
Found in a complex with TOM1; interacts (via N-terminus) with TOM1 (via GAT domain); the interactions leads to TOM1-recruitment to endosomes and inhibition of TOLLIP binding to PtdIns(3)P (PubMed:14563850, 15047686, 26320582, 31263572).
Interacts with TOM1L2 (PubMed:16412388).
Interacts with ATG8 family proteins (via AIM motifs) (PubMed:25042851).
Interacts (via CUE domain) with ubiquitin (PubMed:14563850, 25042851).
Interacts with LRBA (PubMed:31263572).