TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88–independent TLR4 pathway

Pålsson-McDermott, Eva M.; Doyle, Sarah; McGettrick, Anne F.; Hardy, Matthew P.; Husebye, Harald; Banahan, Kathy; Gong, Mei; Golenbock, Douglas T.; Espevik, Terje; O’Neill, Luke A. J.

doi:10.1038/ni.1727

Cited by 128 publications

(120 citation statements)

References 30 publications

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“…Secretion of TNF-α and IL-6 induced by LPS or UT12 was significantly diminished in MyD88 −/− macrophages, but IFN-β and IP-10 levels were either equivalent to or slightly less in MyD88 −/− compared with WT macrophages (Fig. S4B), consistent with the classification of IFN-β and IP-10 as MyD88-independent (8,19). In TRIF −/− macrophages, both MyD88-dependent (TNF-α and IL-6) and TRIF-dependent (IFN-β and IP-10) cytokines induced by LPS or UT12 were completely inhibited (Fig.…”

Section: Resultssupporting

confidence: 74%

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Rajesh

Perkins

Ireland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

104

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Dimerization of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) heterodimers is critical for both MyD88-and TIRdomain-containing adapter-inducing IFN-β (TRIF)-mediated signaling pathways. Recently, Zanoni et al. [(2011) Cell 147(4):868-880] reported that cluster of differentiation 14 (CD14) is required for LPS-/Escherichia coli-induced TLR4 internalization into endosomes and activation of TRIF-mediated signaling in macrophages. We confirmed their findings with LPS but report here that CD14 is not required for receptor endocytosis and downstream signaling mediated by TLR4/MD2 agonistic antibody (UT12) and synthetic small-molecule TLR4 ligands (1Z105) in murine macrophages. CD14 deficiency completely ablated the LPS-induced TBK1/IRF3 signaling axis that mediates production of IFN-β in murine macrophages without affecting MyD88-mediated signaling, including NF-κB, MAPK activation, and TNF-α and IL-6 production. However, neither the MyD88-nor TRIF-signaling pathways and their associated cytokine profiles were altered in the absence of CD14 in UT12-or 1Z105-treated murine macrophages. Eritoran (E5564), a lipid A antagonist that binds the MD2 "pocket," completely blocked LPS-and 1Z105-driven, but not UT12-induced, TLR4 dimerization and endocytosis. Furthermore, TLR4 endocytosis is induced in macrophages tolerized by exposure to either LPS or UT12 and is independent of CD14. These data indicate that TLR4 receptor endocytosis and the TRIF-signaling pathway are dissociable and that TLR4 internalization in macrophages can be induced by UT12, 1Z105, and during endotoxin tolerance in the absence of CD14. T oll-like receptor 4 (TLR4) signaling plays a crucial role in host defense against Gram-negative bacteria by recognizing the outer membrane component, lipopolysaccharide (LPS) (1-3). TLR4 signaling is initiated by transfer of an LPS monomer from LPS binding protein (LBP) to cluster of differentiation 14 (CD14) (GPI-linked or soluble). In turn, CD14 transfers monomeric LPS to myeloid differentiation factor 2 (MD-2), a protein that associates noncovalently with TLR4 (4). Appropriate ligand binding to MD2 results in dimerization of two TLR4/MD2 complexes (4). TLR4 is unique in that it is the only TLR that activates both myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing IFN-β (TRIF)-dependent signaling pathways (5, 6). MyD88-mediated, TLR4 signaling occurs mainly at plasma membranes and involves IL-1R-associated kinases phosphorylation, association of TNF-receptor-associated factor 6, and downstream signaling that results in NF-κB activation and induction of proinflammatory mediators such as TNF-α and IL-6 (7). In contrast, TRIF-mediated signaling in response to LPS occurs at the endosomal membrane after internalization of the TLR4 that, in turn, activates IFN regulatory factor 3 (IRF3), resulting in production of IFN-β, IP-10, and other IRF-3-dependent genes, as well as delayed NF-κB activation (8). Recent studies have shown that the endocytosis of TLR4 is tight...

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Section: Resultssupporting

confidence: 74%

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Rajesh

Perkins

Ireland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

104

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“…TRAM adaptor with GOLD (TAG) domain and transmembrane emp24 domain-containing protein 7 (TMED7) have been reported to be involved in the regulation of TRIFdependent TLR4 pathway. Transmembrane emp24 domaincontaining protein 7interacts with TRAM and displaces the TRIF from TRAM in endosomes (31). TMED7 colocalizes with TRAM and TLR4 in endosomes, where it encounters TAG and mediates the inhibitory effects of TAG on TRAM-TRIF association (32).…”

Section: Discussionmentioning

confidence: 99%

Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM

Huai

Song

Wang

et al. 2015

The Journal of Immunology

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TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. However, the mechanisms by which TRAM links downstream molecules are not fully elucidated. In this study, we show that TRAM undergoes tyrosine phosphorylation upon TLR4 activation and that is required for TLR4-induced IRF3 activation. Protein tyrosine phosphatase nonreceptor type 4 (PTPN4), a protein tyrosine phosphatase, inhibits tyrosine phosphorylation and subsequent cytoplasm translocation of TRAM, resulting in the disturbance of TRAM–TRIF interaction. Consequently, PTPN4 specifically inhibits TRIF-dependent IRF3 activation and IFN-β production in TLR4 pathway. Therefore, our results provide new insight into the TLR4 pathway and identify PTPN4 as a specific inhibitor of TRIF-dependent TLR4 pathway. Targeting PTPN4 would be beneficial for the development of new strategy to control TLR4-associated diseases without unwanted side effects.

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“…Wild-type and IL-10-deficient bone marrow obtained from Peter Murray (University of Memphis) were isolated from the tibias and femurs of C57/Bl6 mice, and primary BMDM were generated as described previously (11). Human peripheral blood mononuclear cells (hPBMC) were isolated from whole blood using a Ficoll gradient (21). Splenocytes from wild-type and E-miR-155 transgenic mice, obtained from Carlo Croce (Ohio State University), were maintained in RPMI and 50 M ␤-mercaptoethanol.…”

mentioning

confidence: 99%

IL-10 Inhibits miR-155 Induction by Toll-like Receptors

McCoy

Sheedy

Qualls

et al. 2010

Journal of Biological Chemistry

232

180

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IL-10 is a potent anti-inflammatory cytokine that is crucial for down-regulating pro-inflammatory genes, which are induced by Toll-like receptor (TLR) signaling. In this study, we have examined whether modulation of microRNAs plays a role in the inhibitory effect of IL-10 on TLR4 signaling. Analyzing microRNAs known to be induced by TLR4, we found that IL-10 could inhibit the expression of miR-155 in response to lipopolysaccharide but had no effect on miR-21 or miR-146a. IL-10 inhibited miR-155 transcription from the BIC gene in a STAT3-dependent manner. This inhibitory effect of IL-10 on miR-155 led to an increase in the expression of the miR-155 target, SHIP1. This is the first example of IL-10 playing a role in microRNA function and suggests that through its inhibitory effect on miR-155, IL-10 has the ability to promote anti-inflammatory gene expression.

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TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88–independent TLR4 pathway

Cited by 128 publications

References 30 publications

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM

IL-10 Inhibits miR-155 Induction by Toll-like Receptors

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