TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2

Li, Xiaoming; Yang, Yili; Ashwell, Jonathan D.

doi:10.1038/416345a

Cited by 427 publications

(401 citation statements)

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“…Whether TRAF2 negatively regulates signaling beyond competing with other signaling proteins for GITR binding is unclear. Intriguingly, TRAF2 has been shown recently to function as an E3 ubiquitin ligase and to undergo ubiquitination itself (42,54,55). Future studies will test whether ubiquitination of TRAF2 or other proteins plays a role in the novel regulatory role of TRAF2 in GITR-induced NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Esparza

Arch

2005

The Journal of Immunology

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Glucocorticoid-induced TNFR (GITR) has been implicated as an essential regulator of immune responses to self tissues and pathogens. We have recently shown that GITR-induced cellular events promote survival of naive T cells, but are insufficient to protect against activation-induced cell death. However, the molecular mechanisms of GITR-induced signal transduction that influence physiologic and pathologic immune responses are not well understood. TNFR-associated factors (TRAFs) are pivotal adapter proteins involved in signal transduction pathways of TNFR-related proteins. Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor. GITR-induced activation of NF-κB is blocked by A20, an NF-κB-inducible protein that interacts with TRAFs and functions in a negative feedback mechanism downstream of other TNFRs. Interestingly, in contrast with its effects on signaling triggered by other TNFRs, our functional studies revealed that TRAF2 plays a novel inhibitory role in GITR-triggered NF-κB activation.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Esparza

Arch

2005

The Journal of Immunology

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“…It has been shown that the binding of TNF to TNFR2 induces ubiquitination of TRAF2 by c-IAP1 and subsequent proteasomal degradation of TRAF2 [51]. Thus, TNFR2 skews the signal of TNFR1 toward death by degradation of TRAF2.…”

Section: Discussionmentioning

confidence: 99%

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

et al. 2009

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TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4 + T-cell transfer model of colitis using TNFR2 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.Key words: CD4 1 T cells Á Inflammation Á Intestinal immunity Á TNF Introduction TNF plays a fundamental role in immunity and inflammation based on its pleiotropic effects on differentiation, growth and apoptotic cell death of both immune and non-immune cell subsets [1,2]. It is well established that TNF is also critically involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, MS and inflammatory bowel diseases (IBD) [3]. Monocytes and macrophages are the main producers of TNF, but T and B lymphocytes and also mast cells can produce significant amounts of TNF. Interestingly, intestinal cell lines are induced to synthesize TNF upon infection with invasive bacterial strains [4]. TNF mediates its functions by binding as a trimer to either TNF receptor (TNFR) 1 or 2. The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types. The intracellular domain of TNFR1 contains a death domain (DD) that leads to apoptosis through caspase activation. TNFR1 signaling can also mediate transcription of anti-apoptotic proteins, inflammatory cytokines and chemokines through activation of NF-kB. The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is Eur. J. Immunol. 2009. 39: 1743-1753 DOI 10.1002 Cellular immune response 1743 expressed predominantly by haematopoietic cells, but expression by other cell types can be i...

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“…We then determined if the effect of Gα o on the ubiquitination of RGS20 was specific by comparing the result of Gα o -Q/L expression on RGS20 to a well known ubiquitinated protein, Traf2 [15]. Under conditions where Gα o -Q/L stimulated the ubiquitination of RGS20 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Gαo/i-stimulated proteosomal degradation of RGS20: A mechanism for temporal integration of Gs and Gi pathways

Pagano

Jordan

Neves

et al. 2008

Cellular Signalling

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The G s and G i pathways interact to control the levels of intracellular cAMP. Although coincident signaling through G s and G i -coupled receptors can attenuate G s -stimulated cAMP levels, it is not known if prior activation of the G i pathway can affect signaling by G s -coupled receptors. We have found that activated Gα o/i interact with RGS20, a GTPase activating protein for members of the Gα o/i family. Interaction between Gα o/i and RGS20 results in decreased cellular levels of RGS20. This decrease was induced by activated Gα o and Gα i2 but not by Gα q , Gα i1 or Gα i3. The Gα o/iinduced decrease in RGS20 can be blocked by proteasomal inhibitors lactacystin or MG132. Activated Gα o stimulates the ubiquitination of RGS20. The serotonin-1A receptor that couples to G o/i reduces the levels of RGS20 and this effect is blocked by lactacystin, suggesting that G o/i promotes the degradation of RGS20. Expression of RGS20 attenuates the inhibition of β-adrenergic receptor-induced cAMP levels mediated by the serotonin-1A receptor. Prior activation of the serotonin-1A receptor results in loss of the RGS20-mediated attenuation, and the loss of attenuation is blocked when lactacystin is included during the prior treatment. These observations suggest that G o/i -coupled receptors, by stimulating the degradation of RGS20, can regulate how subsequent activation of the G s and G i pathways controls cellular cAMP levels, thus allowing for signal integration.

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TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2

Cited by 427 publications

References 30 publications

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

Gαo/i-stimulated proteosomal degradation of RGS20: A mechanism for temporal integration of Gs and Gi pathways

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TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2

Cited by 427 publications

References 30 publications

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

Gαo/i-stimulated proteosomal degradation of RGS20: A mechanism for temporal integration of Gs and Gi pathways

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Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis