Toll-like Receptors (TLRs) Pathway

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. They participate in the first line of defense against invading pathogens and play a significant role in inflammation, immune cell regulation, survival, and proliferation. To date 11 members of the TLR family have been identified, of which TLR1, TLR2, TLR4, TLR5, and TLR6 are located on the cell surface and TLR3, TLR7, TLR8, and TLR9 are localized to the endosomal/lysosomal compartment. The activation of the TLR signaling pathway originates from the cytoplasmic Toll/IL-1 receptor (TIR) domain that associates with a TIR domain-containing adaptor, MyD88. Upon stimulation with ligands, MyD88 recruits IL-1 receptor-associated kinase-4 (IRAK-4) to TLRs through interaction of the death domains of both molecules. IRAK-1 activated by phosphorylation then associates with TRAF6, finally leading to activation of MAP kinases (JNK, p38 MAPK) and NF-κB. Tollip and IRAK-M interact with IRAK-1 and negatively regulate the TLR-mediated signaling pathways. Additional modes of regulation for these pathways include TRIF-dependent induction of TRAF6 signaling by RIP1 and negative regulation of TIRAP mediated downstream signaling by ST2L, TRIAD3A, and SOCS1. MyD88-independent pathways induce activation of IRF3 and expression of interferon-β. TIR-domain containing adaptors such as TIRAP, TRIF, and TRAM regulate TLR-mediated signaling pathways by providing specificity for individual TLR signaling cascades.

Selected Reviews:

• Barton GM, Kagan JC (2009) A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat. Rev. Immunol. 9(8), 535–42.
• Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32(3), 305–15.
• Li X, Jiang S, Tapping RI (2010) Toll-like receptor signaling in cell proliferation and survival. Cytokine 49(1), 1–9.
• McGettrick AF, O'Neill LA (2010) Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr. Opin. Immunol. 22(1), 20–7.
• Miggin SM, O'Neill LA (2006) New insights into the regulation of TLR signaling. J. Leukoc. Biol. 80(2), 220–6.
• Pasare C, Medzhitov R (2005) Toll-like receptors: linking innate and adaptive immunity. Adv. Exp. Med. Biol. 560, 11–8.

We would like to thank Dr. Pranoti Mandrekar, University of Massachusetts Medical School, Worcester, MA, for contributing to this diagram.