TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β

Kagan, Jonathan C.; Su, Tian; Horng, Tiffany; Chow, Amy; Akira, Shizuo; Medzhitov, Ruslan

doi:10.1038/ni1569

Cited by 1,084 publications

(1,248 citation statements)

References 51 publications

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“…ApoER2' may also facilitate endocytosis and signal transduction [73]. While the internalization of TLR4 is required for optimal activity in response to a wide variety of ligands [74,75], our data also suggest that TLR2 endocytosis in monocytes also provides an optimal mechanism for monocyte activation by TLR2 ligands, including aPLA (Brandt et al, submitted). Adding further to the complexity regarding the interaction of TLRs with their respective ligands is the observation that specific TLRs may interact with co-receptors of other TLRs.…”

Section: Internalization and Apla Receptorssupporting

confidence: 53%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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Section: Internalization and Apla Receptorssupporting

confidence: 53%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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“…Once TLR3 is activated by dsRNA, TICAM-1 transiently colocalizes with TLR3 on the cell surface or on the endosomes [46]. The localization of TICAM-2 on endosomes is both necessary and sufficient to induce TLR4 signaling and support a model whereby LPS induces the internalization of TLR4 into endosomes when the TRAM-TRIF-dependent signaling pathway is activated [28]. For amphioxus, the crucial formation of homodimer in endosomes, which is determined by both the TIR domain and C-terminal domain, is important for its function, indicating that the primitive TICAM path in amphioxus has set up the functional foundation for the endosomal TLRs, which chiefly participate in cellular virus detection through induction of IFNs.…”

Section: Gradual Adaptation Of the Myd88-independent Pathway With Thementioning

confidence: 86%

“…In mammals, the delivery of TICAM2 to endosomes is a requisite step in the TLR4-TICAM2-TICAM1 pathway [28]. To further investigate the mechanism of bbt-TICAM, and to discover if its subcellular localization is similar to that of mammalian TICAM1 and TICAM2, Hela cell line were co-transfected with bbtTICAM and the endosome marker, CD63.…”

Section: Activity Of Bbtticam Depends On Its Tir Domain and C Terminumentioning

confidence: 99%

Characterization of bbtTICAM from amphioxus suggests the emergence of a MyD88-independent pathway in basal chordates

et al. 2011

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The MyD88-independent pathway, one of the two crucial TLR signaling routes, is thought to be a vertebrate innovation. However, a novel Toll/interleukin-1 receptor (TIR) adaptor, designated bbtTICAM, which was identified in the basal chordate amphioxus, links this pathway to invertebrates. The protein architecture of bbtTICAM is similar to that of vertebrate TICAM1 (TIR-containing adaptor molecule-1, also known as TRIF), while phylogenetic analysis based on the TIR domain indicated that bbtTICAM is the oldest ortholog of vertebrate TICAM1 and TICAM2 (TIR-containing adaptor molecule-2, also known as TRAM). Similar to human TICAM1, bbtTICAM activates NF-κB in a MyD88-independent manner by interacting with receptor interacting protein (RIP) via its RHIM motif. Such activation requires bbtTICAM to form homodimers in endosomes, and it may be negatively regulated by amphioxus SARM (sterile α and armadillo motif-containing protein) and TRAF2. However, bbtTICAM did not induce the production of type I interferon. Thus, our study not only presents the ancestral features of vertebrate TICAM1 and TI-CAM2, but also reveals the evolutionary origin of the MyD88-independent pathway from basal chordates, which will aid in understanding the development of the vertebrate TLR network.

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“…MyD88 oligomerization and recruitment of specific kinases leads to the formation of myddosomes, signalling platforms that induce NF‐κB translocation into the nucleus and subsequent transcription of pro‐inflammatory associated genes (Nagpal et al , 2011; Bonham et al , 2014). TLR4 activation also results in induction of a type I IFN via another set of adaptors, TRAM and TRIF (Fitzgerald et al , 2001; Yamamoto et al , 2002; Kagan et al , 2008). In the case of the MyD88‐dependent TLR5, the identity of a sorting adaptor remains undefined and the role of TIRAP unclear although it has been implicated in proper TLR5 signalling in epithelial cells (Choi et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

et al. 2017

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Bacterial pathogens often subvert the innate immune system to establish a successful infection. The direct inhibition of downstream components of innate immune pathways is particularly well documented but how bacteria interfere with receptor proximal events is far less well understood. Here, we describe a Toll/interleukin 1 receptor (TIR) domain‐containing protein (PumA) of the multi‐drug resistant Pseudomonas aeruginosa PA7 strain. We found that PumA is essential for virulence and inhibits NF‐κB, a property transferable to non‐PumA strain PA14, suggesting no additional factors are needed for PumA function. The TIR domain is able to interact with the Toll‐like receptor (TLR) adaptors TIRAP and MyD88, as well as the ubiquitin‐associated protein 1 (UBAP1), a component of the endosomal‐sorting complex required for transport I (ESCRT‐I). These interactions are not spatially exclusive as we show UBAP1 can associate with MyD88, enhancing its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes both cytokine and TLR receptor signalling, highlighting a novel strategy for innate immune evasion.

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TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β

Cited by 1,084 publications

References 51 publications

Receptors involved in cell activation by antiphospholipid antibodies

Receptors involved in cell activation by antiphospholipid antibodies

Characterization of bbtTICAM from amphioxus suggests the emergence of a MyD88-independent pathway in basal chordates

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

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