Phosphatases in toll-like receptors signaling: the unfairly-forgotten

Abstract

Over the past 2 decades, pattern recognition receptors (PRRs) have been shown to be on the front line of many illnesses such as autoimmune, inflammatory, and neurodegenerative diseases as well as allergies and cancer. Among PRRs, toll-like receptors (TLRs) are the most studied family. Dissecting TLRs signaling turned out to be advantageous to elaborate efficient treatments to cure autoimmune and chronic inflammatory disorders. However, a broad understanding of TLR effectors is required to propose a better range of cures. In addition to kinases and E3 ubiquitin ligases, phosphatases emerge as important regulators of TLRs signaling mediated by NF-κB, type I interferons (IFN I) and Mitogen-Activated Protein Kinases signaling pathways. Here, we review recent knowledge on TLRs signaling modulation by different classes and subclasses of phosphatases. Thus, it becomes more and more evident that phosphatases could represent novel therapeutic targets to control pathogenic TLRs signaling. Video Abstract.

Keywords: IFN I; IRFs axis; MAPK; NF-κB; Phosphatases; TLRs; Toll-like receptors.

Fig. 1

Tyrosine phosphorylation following TLRs engagement. Activated FAK phosphorylates BTK, opening its conformation and allowing its phosphorylation and activation by Src kinases [29, 30]. BTK can then phosphorylate adaptor proteins such as TIRAP

Fig. 2

Regulation of TLR/MyD88-dependent pathways by phosphatases. TLRs localized at the plasma membrane use the bridging adapter TIRAP to recruit MyD88 and activate the NF-κB and MAPK pathways. MyD88 then recruits IRAK4 which phosphorylates IRAK1 which activates TRAF6. TRAF6 induces K63-linked polyubiquitination of TRAF6 itself serving as a platform leading to TAK1 autophosphorylation and activation. Activated TAK1 phosphorylates IKK-α and IKK-β which induce IκBα degradation, allowing NF-κB nuclear translocation and induction of proinflammatory genes transcription. TAK1 also phosphorylates the MAPK Kinases MKK3, MKK4, MKK6 and MKK7, resulting in activation and nuclear translocation of MAP Kinases which phosphorylate several transcription factors inducing proinflammatory mediator genes transcription

Fig. 3

Regulation of TLR/TRIF-dependent pathways by phosphatases. TRIF is recruited directly to TLR3 but indirectly, via TRAM adaptor, to TLR4, following stimulation. TRIF adaptor then recruits TRAF3 which induces K63-linked ubiquitination of TBK1, its autophosphorylation and then, activation. Activated TBK1 then phosphorylates the transcription factors IRF3 and IRF7, leading to homodimerization or heterodimerization, translocation into the nucleus and target genes induction, including IFNI. TLR7, TLR8 and TLR9 activate the TRIF-dependent pathways via the MyD88 adaptor