Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors

Chuang, Tsung‐Hsien; Ulevitch, Richard J.

doi:10.1038/ni1066

Cited by 338 publications

(302 citation statements)

References 48 publications

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“…Indeed, TLR4 was shown to be ubiquitinated and marked for degradation in human embryonic kidney 293 cells. 30 TLR4 IR did not correlate with histological tumor type, WHO grade or PI. However, it positively correlated with the antiproliferative response to paclitaxel.…”

Section: Discussionmentioning

confidence: 92%

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

Tichomirowa

Theodoropoulou

Daly

et al. 2008

Intl Journal of Cancer

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Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and radiotherapy are main treatment options, but meningiomas may be impossible to adequately resect or may regrow after surgery. In spite of many experimental attempts, there is no generally accepted chemotherapeutic approach. We have studied in a series of meningiomas the expression of the Toll-like receptor 4 (TLR4), which apart from its major role as a key factor of the innate immune system, is believed to play a role in tumorigenesis. All meningiomas studied expressed TLR4 mRNA and protein at variable degree. Paclitaxel, a ligand of TLR4, exhibited a dose-and time-dependent growth suppression in both monolayer and spheroid meningioma cell cultures. The knockdown of TLR4 with siRNA in meningioma cell cultures abrogated the inhibitory effect of paclitaxel. The suppressive action of paclitaxel on meningioma cell growth was enhanced in the presence of fluvastatin or the mitogen-actvated protein kinase (ERK1/2) inhibitor PD98059. At least part of the growth suppressive effect was mediated by the induction of apoptosis in meningioma cells by paclitaxel alone or in combination with fluvastatin. In conclusion, our in vitro results suggest that paclitaxel alone or in combination with other inhibitors of cell growth (statins, MAPK inhibitors) could provide a potential tool for the treatment of TLR4 expressing meningiomas.

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Section: Discussionmentioning

confidence: 92%

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

Tichomirowa

Theodoropoulou

Daly

et al. 2008

Intl Journal of Cancer

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“…One cannot assume a protein will bind all TIR domain-containing proteins if it binds the TIR derived from TLR4. For example, Triad3A binds TLR3, 4, 5, and 9, but not TLR2 (28). Furthermore, the mammalian two-hybrid assay we used is highly sensitive yet artificial.…”

Section: Discussionmentioning

confidence: 99%

“…Our data indicate that Fliih exerts an inhibitory effect on the TLR4-MyD88 signaling pathway by interfering with the formation of the TLR4-MyD88 signaling complex. Unlike ST2 and Triad3A, whose effects are restricted to certain TLRs (14,28), Fliih seems to inhibit TLR pathways in general. This is not surprising because Fliih was found to interact with MyD88, TRIF, and the TIR domain derived from TLR4 in the mammalian two-hybrid assay.…”

Section: Discussionmentioning

confidence: 99%

Flightless I Homolog Negatively Modulates the TLR Pathway

Wang

Chuang

Ronni

et al. 2006

The Journal of Immunology

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To date, much of our knowledge about the signaling networks involved in the innate immune response has come from studies using nonphysiologic model systems rather than actual immune cells. In this study, we used a dual-tagging proteomic strategy to identify the components of the MyD88 signalosome in murine macrophages stimulated with lipid A. This systems approach revealed 16 potential MyD88-interacting partners, one of which, flightless I homolog (Fliih) was verified to interact with MyD88 and was further characterized as a negative regulator of the TLR4-MyD88 pathway. Conversely, a reduction in endogenous Fliih by small-interfering RNA enhanced the activation of NF-κB, as well as cytokine production by LPS. Results from immunoprecipitation and a two-hybrid assay further indicated that Fliih directly interfered with the formation of the TLR4-MyD88 signaling complex. These results in turn suggest a new basis for the regulation of the TLR pathway by Fliih.

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“…In addition to IRAK-M, many negative regulators of TLR signaling have been identified, including the TLR homolog RP105, Src homology 2-containing inositol-5′-phosphatase (SHIP), short form of MyD88, ST2, SIGIRR, Triad3A, A20, and SOCS-1 (44)(45)(46)(47)(48)(49)(50)(51)(52). Many of these molecules have been implicated in the development of endotoxin tolerance.…”

Section: Figurementioning

confidence: 99%

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Deng

Cheng

Newstead

et al. 2006

Journal of Clinical Investigation

166

252

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Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonas aeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M -/-animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M -/-animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

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Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors

Cited by 338 publications

References 48 publications

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

Flightless I Homolog Negatively Modulates the TLR Pathway

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

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