Toll-like receptor signaling pathways

Abstract

Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.

Keywords: IRFs; NF-κB; TLRs; adaptors; signal transduction.

Figure 1

TLR signaling in cDCs, macrophages, and MEFs. TLR4 localize to the cell surface, and TLR3 localize in the endosome compartment. Homo- or heterodimer formation initiates signaling to the two major downstream adaptor proteins, MyD88 and TRIF. TIRAP conducts the signal from TLR4 to MyD88, and TRAM mediates the signal from TLR4 to TRIF. TLR engagement induces formation of the Myddosome, which is based on MyD88 and also contains IRAK1 and IRAK4. IRAK1 activation induces TRAF6 activation following K63-linked polyubiquitination on TRAF6 itself and TAK1. TAK1 activation leads to the activation of IKK complex-NF-κB and MAPKs. MAPK activation leads to AP1s transcription factor activation. TRAF6 promotes ECSIT ubiquitination, resulting in increased mitochondrial and cellular ROS generation. TLR engagement also induces TRIF activation following TRAF6 and TRAF3 recruitment. TRAF6 recruits RIP-1, which activates the TAK1 complex following MAPK activation. RIP-1 activation regulates ubiquitination by Pellino-1. Pellino-1 regulates IRF3 activation by binding to DEAF-1. TRAF3 recruits TBK1 and IKKi for IRF3 phosphorylation. PtdIns5P from PIKfyve facilitates complex formation between TBK1 and IRF3. Several negative regulators modulate TLR signaling, by inhibiting either signaling complex formation or ubiquitination. MyD88 is suppressed by ST2825, NRDP-1, SOCS1, and Cbl-b; TRIF is suppressed by SARM and TAG; TRAF3 is suppressed by SOCS3 and DUBA; and TRAF6 is suppressed by A20, USP4, CYLD, TANK, TRIM38, and SHP. NF-κB is suppressed by Bcl-3, IκBNS, Nurr1, ATF3, and PDLIM2, while IRF3 activation is negatively regulated by Pin1 and RAUL.

Figure 2

Intracellular TLR signaling and trafficking in pDCs. Activation of TLR7 or TLR9 in pDCs recruits MyD88 following IRAK4 recruitment. The MyD88 complex also contains TRAF3, TRAF6, IRAK4, IRAK1, IKKα, OPNi, and Dock2. MyD88 directly or indirectly recruits IRF7 to be phosphorylated by IKKα and/or IRAK1. Localization of TLR7 and 9 is controlled by UNC93B1, PRAT4A, and AP3, which traffic TLRs from the ER to the endosome or the lysosome-related organelle (LRO). In the endosome, TLRs are converted to their mature forms by cathepsins, which cleave LRRs in the ectodomain. pDCs utilize a distinct signaling pathway from that in cDCs or macrophages to induce the synthesis of large amount of type I IFNs. gp96, a member of the ER-resident heat-shock protein 90 family, functions as a general chaperone for most TLRs.