Phosphatases in Toll-Like Receptors Signaling: the Unfairly-Forgotten
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Lannoy et al. Cell Commun Signal (2021) 19:10 https://doi.org/10.1186/s12964-020-00693-9 REVIEW Open Access Phosphatases in toll-like receptors signaling: the unfairly-forgotten Valérie Lannoy, Anthony Côté‑Biron, Claude Asselin and Nathalie Rivard* 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, infammatory, 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 advanta‑ geous to elaborate efcient treatments to cure autoimmune and chronic infammatory disorders. However, a broad understanding of TLR efectors 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 diferent classes and subclasses of phosphatases. Thus, it becomes more and more evident that phos‑ phatases could represent novel therapeutic targets to control pathogenic TLRs signaling. Keywords: Toll‑like receptors, TLRs, Phosphatases, NF‑κB, IRFs axis, IFN I, MAPK Background Polymorphisms (SNPs) of TLRs, their co-receptors and Toll-Like Receptors (TLRs) belong to the Pattern Rec- some adaptors are indeed associated with several dis- ognition Receptors (PRRs) superfamily that recognizes eases including infections, atherosclerosis, asthma, Microbe-Associated Molecular Patterns (MAMPs)—not chronic cardiomyopathy and colorectal cancer [6, 7]. necessarily found on pathogens—, PAMPs (Pathogen) TLRs are divided into two groups: those localized at the and DAMPs (Damage) [1]. Tere are 13 identifed TLRs plasma membrane and those localized at the endosomal in mammals playing an instrumental role in the regula- membrane [8]. Plasma membrane-localized TLRs recog- tion of the innate immune system [2]. Tese receptors nize conserved motifs on extracellular microorganisms are highly conserved proteins also found in the phy- such as bacteria, fungi, protozoan and helminth parasites lum Cnidaria, including jellyfshes [3]. As TLRs evolved [9]. Yet, plasma membrane TLRs are also able to bind before the adaptive immune system, they constitute an DAMPs. Te most glaring example is TLR4 that is well- indispensable frst line of defense [4]. Accordingly, TLRs known to recognize Lipopolysaccharide (LPS), a com- expression is not restricted to immune cell lineages. ponent of Gram-negative bacteria, and 28 other ligands TLR3 and TLR5 mRNAs are detected ubiquitously within including DAMPs [10]. Tis wide range of recognition is the human body, while other TLRs are mostly expressed allowed by combinations between TLRs homodimers or in epithelial tissues (except TLR10, more restricted) [5]. heterodimers with co-receptors and/or accessory mol- Tus, because they constitute the frst line of defense ecules [11]. Te other plasma membrane TLRs include against microbes (see below), TLRs are involved in patho- TLR1, TLR2 and TLR6 which bind various lipopeptides genesis of various disorders. Several Single Nucleotide from Gram-positive bacteria and TLR5 which binds fagellin from fagellated bacteria [9]. Endosomal TLRs (TLR3, TLR7, TLR8, TLR9) are acti- *Correspondence: [email protected] Department of Immunology and Cell Biology, Cancer Research Pavilion, vated by nucleic acids derived from microbes. Teir ecto- Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, domains undergo proteolytic cleavage in endosomes to rue Jean Mignault, Sherbrooke, QC J1E4K8, Canada generate functional receptors for nucleic acid structures © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lannoy et al. Cell Commun Signal (2021) 19:10 Page 2 of 15 [12]. For instance, TLR3 recognizes double stranded suggesting that FAK activation occurs early after TLR RNA (dsRNA), TLR7 and TLR8 recognize single activation [23]. FAK is indeed required for TLR4 down- stranded RNA (ssRNA) and TLR9 binds unmethylated stream signaling since cytokine induction in response to cytidine-phosphate-guanosine (CpG) dinucleotides [13]. LPS is totally abrogated in Fak−/− cells. However, FAK Notably, half of the TLRs exhibit both plasma mem- does not possess TIR domains for direct interaction with brane and endosomal localizations. For instance, in intes- MyD88 or TLR4 [24]. Instead, activated FAK phosphoryl- tinal epithelial cells exposed to bacterial DNA, TLR9 ates BTK which interacts with the TIR domains of TLR4 moves from the endosomal compartment to the cyto- (but also of TLR6, 8, and 9) [25]. BTK phosphorylation by plasmic membrane [14]. In macrophages, membrane- FAK opens its conformation [26] allowing its phospho- associated TLR4 reaches the endosomal compartment rylation and activation by Src kinases (Fig. 1). Once acti- through endocytosis [15]. A similar process has been vated, BTK phosphorylates diferent adapter molecules described for TLR2 which is endocytosed after its heter- such as the bridging adapter TIRAP, facilitating Myd88 odimerization with TLR1 or TLR6 in myeloid cells [16]. recruitment to TLR4 [27]. Interestingly, BTK can also Binding of ligands to TLRs triggers the activation of phosphorylate TLR3 and this is required for downstream several intracellular signaling pathways involving pro- signaling [28]. However, BTK does not phosphorylate tein phosphorylation, dephosphorylation and ubiquit- TRIF, but rather facilitates TRIF interaction with efec- ination. While the roles of specifc protein kinases in this tors Since BTK expression is restricted to myeloid cells, process have been well described [17, 18], much less is ETK, a member of the TEC family of tyrosine kinases, known about the implications of phosphatases, particu- is suspected to play similar functions in other cell types larly tyrosine phosphatases. In this review, we summarize such as epithelial cells. how specifc phosphatases regulate TLRs signaling and Aside from these observations, tyrosine phospho- function. rylation of TLR3 and TLR4 also increased in response to EGF (Epidermal Growth Factor), and inhibition of TLR signaling pathways: an overview EGFR (EGF Receptor) kinase activity impaired activa- Rapid tyrosine phosphorylation following TLRs tion of their downstream signaling. In fact, the Src family engagement kinases mediated this crosstalk between EGFR and TLRs, TLRs are type I membrane glycoproteins with an ectodo- triggering the recruitment of adapters and other efector main consisting of Leucine-Rich Repeats (LRRs), respon- proteins [31, 32]. sible for the molecular recognition of ligands [19]. TLRs Altogether, these observations strongly suggest that contain also a cytoplasmic domain called Toll/Interleu- a coordinated interplay should exist between tyrosine kin-1 Receptor (TIR) domain, which recruits several kinases and phosphatases in order to tightly regulate the adapter proteins including Myeloid Diferentiation pri- activation status of TLRs intracellular signaling and cel- mary response 88 (MyD88), Toll/Interleukin-1 Recep- lular function. Below, we summarize the main signaling tor domain-containing Adapter Protein (TIRAP) or pathways activated by TLRs and we discuss how these TIR-domain-containing adapter-inducing Interferon-β pathways are modulated by various tyrosine and serine/ (TRIF). Upon ligand binding, TLRs undergo conforma- threonine phosphatases. tional changes inducing homodimerization or heterodi- merization which unveil TIR domains which can now The MyD88‑dependent signaling recruit and bind diferent downstream signaling efectors TLRs activate two types of pathways to control infam- regulating the host infammatory response [20]. matory responses: the MyD88-dependent pathway Notably, the TIR domain of TLR2, 3, 4, 5, 8 and 9 is activated by all TLRs except TLR3, and the MyD88-inde- rapidly phosphorylated on tyrosine upon stimulation pendent but TRIF-dependent pathway activated directly with their respective ligands. Tis phosphorylation is by TLR3 and indirectly by other TLRs [33, 34]. Impor- required for the recruitment of adapter proteins and sub- tantly, Myd88 contains a TIR domain as observed in most sequent activation of the downstream signaling cascades TLRs, but most TLRs use the bridging adapter TIRAP [17, 21, 22]. Several tyrosine kinases interact with TLRs, to recruit MyD88 [35]. Indeed,