TRAF1 phosphorylation on Serine 139 modulates NF-κB activity downstream of 4-1BB in T cells

Oussa, Nougboli Arias Eustache; Soumounou, Youssouf; Sabbagh, Laurent

doi:10.1016/j.bbrc.2013.01.073

Cited by 13 publications

(14 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to ubiquitination, other post-translational modifications, including phosphorylation and glutathionylation, are also reported to regulate TRAFs in signaling. Phosphorylation of TRAF1 (at Ser 139 in mouse and Ser 146 in human by PKN1) inhibits TNF-R2-dependent tonic NF-κB and JNK signaling in HeLa cells [233], and also has a negative impact on the recruitment of TBK1 to the 4-1BB signaling complex and the subsequent NF-κB activation in T cells [234]. Phosphorylation of TRAF2 (at Ser11 and Ser55 by PKCζ or IKKε, and at Thr117 by PKCδ and PKCε), which promotes K63-linked ubiquitination of TRAF2 and NF-κB activation, has been demonstrated in TNFα signaling or in transformed cells [235][236][237][238].…”

Section: Regulators Of Mrna Stabilitymentioning

confidence: 99%

TRAF molecules in cell signaling and in human diseases

Xie

2013

JMS

386

454

View full text Add to dashboard Cite

The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily. The past decade has witnessed rapid expansion of receptor families identified to employ TRAFs for signaling. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), T cell receptor, IL-1 receptor family, IL-17 receptors, IFN receptors and TGFβ receptors. In addition to their role as adaptor proteins, most TRAFs also act as E3 ubiquitin ligases to activate downstream signaling events. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-κBs (NF-κBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). Compelling evidence obtained from germ-line and cell-specific TRAF-deficient mice demonstrates that each TRAF plays indispensable and non-redundant physiological roles, regulating innate and adaptive immunity, embryonic development, tissue homeostasis, stress response, and bone metabolism. Notably, mounting evidence implicates TRAFs in the pathogenesis of human diseases such as cancers and autoimmune diseases, which has sparked new appreciation and interest in TRAF research. This review presents an overview of the current knowledge of TRAFs, with an emphasis on recent findings concerning TRAF molecules in signaling and in human diseases.

show abstract

Section: Regulators Of Mrna Stabilitymentioning

confidence: 99%

TRAF molecules in cell signaling and in human diseases

Xie

2013

JMS

386

454

View full text Add to dashboard Cite

show abstract

“…Upon receptor ligation, 4-1BB enhances signaling through the T cell receptor ( 18 ). 4-1BB forms a heterotrimer complex consisting of two TNF-receptor associated factor (TRAF)-2 complexes ( 46 ) in conjunction with TRAF-1 ( 47 ). This interaction, through leukocyte specific protein-1 (LSP-1) ( 48 ), potentiates signaling through the c-Jun N-terminal kinase (JNK) pathway ( 49 ), the extracellular signal-regulated kinase (ERK) pathways ( 50 , 51 ), as well as through β-catenin and AKT ( 51 ).…”

Section: The Role Of 4-1bb In the Immune Responsementioning

confidence: 99%

“…This interaction, through leukocyte specific protein-1 (LSP-1) ( 48 ), potentiates signaling through the c-Jun N-terminal kinase (JNK) pathway ( 49 ), the extracellular signal-regulated kinase (ERK) pathways ( 50 , 51 ), as well as through β-catenin and AKT ( 51 ). These signaling pathways converge on the master transcription factor NF-κB to regulate 4-1BB signaling, as well as effector immune responses ( 47 , 52 ). As most of these signals are shared between TNF co-stimulatory receptors, yet none of the others can replicate the phenotypic changes associated with 4-1BB activation, it is likely that additional molecular pathways are triggered by 4-1BB which have yet to be described.…”

Section: The Role Of 4-1bb In the Immune Responsementioning

confidence: 99%

4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity

2015

View full text Add to dashboard Cite

Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co-receptors, which can be targeted to boost tumor immunity. Among these, the co-stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB’s expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized.

show abstract

“… 14 TRAF1 exerts diverse and often conflicting biologic effects that are cell-type- and context-specific. 15 , 16 Numerous studies have provided evidence that TRAF1 participates in the NF- κ B pathway and has an antiapoptotic role in TNF- α -mediated hepatocyte apoptosis. 17 , 18 However, Tsitsikov et al 19 reported marked proliferation of TRAF1-deficient T cells in response to TNF- α treatment and noted that TRAF1-null mice were hypersensitive to TNF-induced skin necrosis.…”

mentioning

confidence: 99%

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury

Zhang

Huang

et al. 2014

Cell Death Dis

View full text Add to dashboard Cite

Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-κB-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.

show abstract

TRAF1 phosphorylation on Serine 139 modulates NF-κB activity downstream of 4-1BB in T cells

Cited by 13 publications

References 28 publications

TRAF molecules in cell signaling and in human diseases

TRAF molecules in cell signaling and in human diseases

4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury

Contact Info

Product

Resources

About