TAK1 Is a Component of the Epstein-Barr Virus LMP1 Complex and Is Essential for Activation of JNK but Not of NF-κB

Uemura, Noriyuki; Kajino, Taisuke; Sanjo, Hideki; Sato, Shintaro; Akira, Shizuo; Matsumoto, Kunihiro; Ninomiya‐Tsuji, Jun

doi:10.1074/jbc.m509834200

Cited by 34 publications

(38 citation statements)

References 28 publications

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“…Previous reports suggest that transforming growth factor ␤-activated kinase 1 (TAK1) is important for LMP1-mediated JNK activation (20,21). In primary B cells, we did not observe a substantial effect of TRAF5 deficiency on TAK1 activation after stimulation of mCD40-LMP1 (Fig.…”

Section: Direct Role Of Traf5 In Lmp1-mediated Jnk Activation and Il-6mentioning

confidence: 51%

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Kraus¹,

Nakano

Bishop

2009

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

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The cytoplasmic signaling protein TNF receptor-associated factor 5 (TRAF5) has been implicated in several biological roles in Tlymphocyte responses. However, a clear connection between in vivo TRAF5 immune cell functions and specific signaling pathways has not been made. This study shows that TRAF5 associated strongly with the viral oncogenic CD40 mimic latent membrane protein 1 (LMP1), in contrast to weaker association with CD40, for which it has been shown to play a modest role. LMP1 uses specific TRAFs differently than CD40, resulting in amplified and dysregulated CD40-like activation of B lymphocytes. When the cytoplasmic domain of LMP1 is expressed as a transgenic replacement for CD40 in mouse B cells, the resulting mouse exhibits measures of B-cell hyperactivity such as splenomegaly, lymphadenopathy, elevated serum IL-6, elevated serum autoantibodies, and abnormal splenic architecture. Thus, in contrast to CD40, TRAF5 may have an important nonredundant role as a positive mediator of LMP1 signaling and functions in B cells. To test this hypothesis, mice were created that express mCD40LMP1 in place of CD40, and are either sufficient or deficient in TRAF5. Results revealed that TRAF5 plays a critical role in LMP1-mediated c-Jun kinase signaling and is required for much of the abnormal phenotype observed in mCD40LMP1 transgenic mice. This is the first report showing a major requirement for TRAF5 in signaling by a specific receptor both in vitro and in vivo, as well as playing an important role in biological function in B lymphocytes.B lymphocyte ͉ latent membrane protein 1 ͉ TNF receptor-associated factor ͉ lymphocyte activation ͉ TNF receptor superfamily T he Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is a functional mimic of CD40 expressed as a six transmembrane receptor on the cell surface (1). LMP1 selfoligomerizes, resulting in constitutive signaling (1, 2). Although LMP1 can initiate signaling without a ligand, the unique nature of its cytoplasmic domain results in sustained and amplified activation independent of its transmembrane regions. Thus, a hybrid molecule in which the transmembrane domains of LMP1 are replaced with the transmembrane and extracellular portions of CD40 induces B-cell activation that is higher and more prolonged than levels achieved by endogenous CD40 (3-5). Expression of LMP1 by B cells also results in increased survival (5, 6) and class switching (7). The heightened activation state caused by LMP1 expression in mice leads to B-cell hyperactivity, resulting in splenomegaly, lymphadenopathy, and production of elevated serum IL-6 and autoantibodies (4). The amplified and constitutive CD40-like signal provided by LMP1 can also contribute to generation of Reed-Sternberg cells (8) and B-cell lymphoma (9).Like CD40, LMP1 binds and uses cytoplasmic adaptor molecules known as TNF receptor-associated factors (TRAFs). Interestingly, LMP1 uses TRAFs 1, 2, and 3 differently than CD40. TRAFs 1 and 2 cooperate to promote certain CD40-mediated signals to B cells, but TRAF3 inhib...

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Section: Direct Role Of Traf5 In Lmp1-mediated Jnk Activation and Il-6mentioning

confidence: 51%

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Kraus¹,

Nakano

Bishop

2009

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

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“…TAK1 has also been shown to be an oncoprotein component of the Epstein-Barr virus latent membrane protein 1 complex (31,32). These findings altogether raise the possibility that TAK1 is a key molecule in virus-related oncogenesis; however, virus infection and oncoproteins dramatically change the intracellular environment.…”

Section: Discussionmentioning

confidence: 67%

Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-κB

Suzuki

Singhirunnusorn

Mori

et al. 2007

Journal of Biological Chemistry

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HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-B and CREB (cAMP-response element-binding protein)/ATF.Transforming growth factor-␤-activated kinase 1 (TAK1) has been shown to play a critical role in these transcription factors. Here, we found that TAK1 was constitutively activated in Tax-positive HTLV-1-transformed T cells. Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. Surprisingly, TAK1 was not involved in the activation of NF-B. On the other hand, JNK and p38 mitogen-activated protein kinases were activated by TAK1. In addition, ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-B.Human T-cell lymphotropic virus type 1 (HTLV-1) 2 is known as the cause of adult T-cell leukemia/lymphoma (ATLL). Infection with this virus results in the activation of several transcriptional factors including NF-B and CREB in host CD4ϩ T cells. In particular, the activation of NF-B correlates with the expression of HTLV-1-derived oncoprotein Tax (1). It has been reported that Tax associates with IKK␥ to activate IB kinase (IKK) complex (2).Transforming growth factor-␤-activated kinase 1 (TAK1) is one of the most characterized MAPK kinase kinase family members and is activated by various cellular stresses, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1 (3-13). It has recently been shown that TAK1 participates in diverse cellular functions, including activation and differentiation of T lymphocytes (14 -17). TAK1 functions as an upstream stimulatory molecule of the JNK, p38, and IKK signaling pathways. We have reported that phosphorylation at Thr-187 is essential for TAK1 activation, and TAK1-binding protein 1 (TAB1) and TAB2 are important for inducing phosphorylation (18). Cheung et al. (12) report that the association of TAB1 with p38␣ negatively regulates TAK1 kinase activity by phosphorylating TAB1 at Ser-423, Thr-431, and Ser-438. On the other hand, TAB2 functions as an adaptor protein to recruit TAK1 to TRAF2 (TNF-␣ receptor-associated factor) and TRAF6 in the TNF-␣ and interleukin-1 signaling pathways, respectively (8,11,13). Recently, TAB3 has been reported as a new TAK1-binding protein (13). This molecule has a structure similar to TAB2 and functions as a supportive protein of TAB2.Various alternations of intracellular functions by infecting HTLV-1 and Tax expression result in the onset of ATLL; however, the molecular mechanisms of these alternations are still unclear. The present study investigated whether TAK1 is involved in Tax-dependent NF-B activation and other signaling pathways in HTLV-1-transformed cells. , and CREB were purchased from Cell Signaling Technology. Phospho-specific anti-TAK1 (Thr-187) and anti-TAB1 (Ser-438) antibodies are described previously (12, 18). Antibody against TAB3 was generat...

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“…Why recruitment of TRAF6 and TAK1 by A52 does not lead to NFB activation is not entirely clear, although LMP1 also recruits TRAF6 and TAK1, via its N-terminal transmembrane region, to activate p38 and not NFB (21). Interestingly, activation of p38 by A52 did not require TRAF6-associated polyubiquitination (Fig.…”

Section: Mechanism Of P38 Mapk Activation By Poxviral A52mentioning

confidence: 98%

“…For example, rotavirus protein VP4 engages TRAF2 to activate NFB while inhibiting TRAF2-dependent JNK activation (23), whereas UL144 from human cytomegalovirus forms a complex with TRAF6 to activate NFB (22). Epstein-Barr virus LMP-1 (latent membrane protein 1) also stimulates p38 activation via TRAF6 as well as activating NFB via engaging TRAF2 and TRAF5 (21). NS5A from hepatitis C virus inhibits TRAF2-dependent NFB activation while engaging TRAF2 to activate MAP kinase (JNK) (37).…”

Section: Discussionmentioning

confidence: 99%

“…A52-mediated p38 MAP kinase activation via cellular TRAF6 likely represents an immune subversion strategy whereby the virus gains a selective advantage by fine-tuning the signaling environment of an infected cell, for example to potentiate TLRinduced production of IL-10, a cytokine that inhibits inflammatory and cell-mediated immune responses and contributes to viral persistence (16). In fact, there are a number of examples of viral manipulation of signaling pathways via TRAFs for herpes viruses (21,22) and for rotavirus (23). However, the mechanism whereby poxviral A52 subverts TRAF6 to activate p38 is unknown.…”

Section: Immune Detection Of Pathogens Such As Viruses Relies On Actimentioning

confidence: 99%

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Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment

Stack

Hurst

Flannery

et al. 2013

Journal of Biological Chemistry

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Background: Activation of p38 MAPK by poxviral A52 is TRAF6-dependent, but the mechanism is unknown. Results: Disruption of either an identified TRAF6-binding motif or of A52 dimerization prevents TRAF6 oligomerization, TAK1 recruitment, and p38 activation. Conclusion: A52 activates p38 MAPK activation by causing TRAF6 oligomerization, leading to TAK1 recruitment. Significance: This work reveals the molecular basis for poxviral activation of p38 MAPK.

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TAK1 Is a Component of the Epstein-Barr Virus LMP1 Complex and Is Essential for Activation of JNK but Not of NF-κB

Cited by 34 publications

References 28 publications

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-κB

Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment

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