IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-κB activation

Song, Yoon‐Jae; Jen, Kai-Yu; Soni, Vikas; Kieff, Elliott; Cahir-McFarland, Ellen

doi:10.1073/pnas.0511096103

Cited by 51 publications

(52 citation statements)

References 51 publications

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“…2A, lane 2). These results indicate that LMP1 activates TRAF6 and results in its auto-ubiquitination and are consistent with a previous report (50). This is not surprising, since LMP1 is able to engage TRAF6 (47) and therefore facilitates TRAF6 dimerization or oligomerization.…”

Section: Resultssupporting

confidence: 93%

TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1

Ning¹,

Campos

Darnay³

et al. 2008

Molecular and Cellular Biology

102

136

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We have recently shown that interferon regulatory factor 7 (IRF7) is activated by Epstein-Barr virus latent membrane protein 1 (LMP1), a member of the tumor necrosis factor receptor (TNFR) superfamily, through receptor-interacting protein-dependent K63-linked ubiquitination (L. E. Huye, S. Ning, M. Kelliher, and J. S. Pagano, Mol. Cell. Biol. 27:2910-2918, 2007). In this study, with the use of small interfering RNA and TNFR-associated factor 6 (TRAF6) knockout cells, we first show that TRAF6 and its E3 ligase activity are required for LMP1-stimulated IRF7 ubiquitination. In Raji cells which are latently infected and express high levels of LMP1 and IRF7 endogenously, expression of a TRAF6 small hairpin RNA construct reduces endogenous ubiquitination and endogenous activity of IRF7. In TRAF6 ؊/؊ mouse embryonic fibroblasts, reconstitution with TRAF6 expression, but not with TRAF6(C70A), which lacks the E3 ligase activity, recovers LMP1's ability to stimulate K63-linked ubiquitination of IRF7. Further, we identify IRF7 as a substrate for TRAF6 E3 ligase and show that IRF7 is ubiquitinated by TRAF6 at multiple sites both in vitro and in vivo. Most important, we determine that the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 variant A are essential for activation of IRF7; these are the first such sites identified. A ubiquitination-deficient mutant of IRF7 with these sites mutated to arginines completely loses transactivational ability in response not only to LMP1 but also to the IRF7 kinase IB kinase . In addition, we find that K63-linked ubiquitination of IRF7 occurs independently of its C-terminal functional phosphorylation sites. These data support our hypothesis that regulatory ubiquitination of IRF7 is a prerequisite for its phosphorylation. This is the first evidence to imply that ubiquitination is required for phosphorylation and activation of a transcription factor. Intracellular signaling initiated by latent membrane protein 1 (LMP1), the principal oncoprotein of the human gammaherpesvirus Epstein-Barr virus (EBV), is of interest not only for viral oncogenesis but also for the reason that LMP1 shares early steps in pathways used by CD40, interleukin-1 (IL-1) receptor-Toll-like receptor (TLR), and tumor necrosis factor receptor (TNFR) for activation of NFB (reviewed in references 16 and 35). As a member of the TNFR superfamily, LMP1 recruits TNFR-associated death domain protein, TNFRinteracting protein (RIP), and several TNFR-associated factors (TRAFs). Unlike CD40 and receptor activator of NF-B (RANK), which contain TRAF6-binding sites, LMP1 does not have a consensus TRAF6-binding sequence but associates with TRAF6 indirectly (reviewed in references 8, 16, 35, 51, and 61).Ubiquitination through K48-polyubiquitin linkage is well known as a process whereby proteins are targeted for proteasomal degradation. Recently, proteasome-independent functions for ubiquitination through K63 polyubiquitin or monoubiquitin linkages have been identified, and the importance of these ubiquitin...

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Section: Resultssupporting

confidence: 93%

TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1

Ning¹,

Campos

Darnay³

et al. 2008

Molecular and Cellular Biology

102

136

View full text Add to dashboard Cite

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“…Alternatively, it is also possible that specific phosphorylation is mediated by other kinases, which are selectively activated by IKK␤ and IKKε. Surprisingly, IKKs, IKK-related kinases, and IRAK1 were previously reported to phosphorylate S 536 or S 468 of RelA under various physiological conditions (28,(60)(61)(62)(63). Our recent studies further validate these phosphorylation events for RelA that occur in KSHV-infected cells.…”

Section: Discussionsupporting

confidence: 75%

NF-κB Activation Coordinated by IKKβ and IKKε Enables Latent Infection of Kaposi's Sarcoma-Associated Herpesvirus

Zhao

Zhang

et al. 2014

J Virol

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All herpesviruses share a remarkable propensity to establish latent infection. Human Kaposi's sarcoma-associated herpesvirus (KSHV) effectively enters latency after de novo infection, suggesting that KSHV has evolved with strategies to facilitate latent infection. NF-B activation is imperative for latent infection of gammaherpesviruses. However, how NF-B is activated during de novo herpesvirus infection is not fully understood. Here, we report that KSHV infection activates the inhibitor of B kinase ␤ (IKK␤) and the IKK-related kinase epsilon (IKK)

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“…TRADD may further stabilize CTAR2 interaction with RIP1, recruit TRAF6 to K63 polyubiquitinate RIP1 and attract IKK␥, TBK1, or IKK . IRAK1 is critical for LMP1 mediated NF-B activation (41,42) and may also have a role in LMP1-mediated IRF7 activation. 7).…”

Section: Discussionmentioning

confidence: 99%

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

Song

Izumi

Shinners

et al. 2008

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

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Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1), a constitutively aggregated and activated pseudoreceptor, activates IFN regulatory factor 7 (IRF7) through RIP1. We now report that the LMP1 cytoplasmic carboxyl terminal amino acids 379 -386 bound IRF7 and activated IRF7. IRF7 activation required TRAF6 and RIP1, but not TRAF2 or TRAF3. LMP1 Y384YD386, which are required for TRADD and RIP1 binding and for NF-B activation, were not required for IRF7 binding, but were required for IRF7 activation, implicating signaling through TRADD and RIP1 in IRF7 activation. Association with active LMP1 signaling complexes was also critical for IRF7 activation because (i) a dominant-negative IRF7 bound to LMP1, blocked IRF7 association and activation, but did not inhibit LMP1 induced NF-B or TBK1 or Sendai virus-mediated IFN stimulated response element activation; and (ii) two different LMP1 transmembrane domain mutants, which fail to aggregate, each bound IRF7 and prevented LMP1 from binding and activating IRF7 in the same cell, but did not prevent NF-B activation. Thus, efficient IRF7 activation required association with LMP1 CTAR2 in proximity to LMP1 CTAR2 mediated kinase activation sites. LMP1 has a 24-aa cytoplasmic N-terminus, six hydrophobic transmembrane domains (amino acids 25 to 186) and a 200-aa cytoplasmic C-terminus (amino acids 187 to 386). The transmembrane domains induce LMP1 aggregation in plasma membrane lipid rafts and barges and constitutively activate two C-terminal cytoplasm signaling domains referred to as C-terminal activation regions (CTAR) or transformation effector sites (TES) 1 and 2, which were initially defined as amino acids 187-231 and 352-386, respectively (Fig. 1A) (2-9). CTAR1 amino acids 201 to 210 engage tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) 1, 3, 2, and 5 and CTAR2 amino acids 376-386 engage TNFRassociated death domain proteins TRADD and RIP1 (4-12). Both signaling domains activate NF-B, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, thereby altering cell gene expression, cell survival, and immune responses (13-17).LMP1 also induces and activates IFN regulatory factor 7 (IRF7) (18-20), a critical transcription factor for type 1 IFN (IFN)-mediated innate and adaptive immune responses (21-24). IRF7 is comprised of DNA binding, constitutive activation, virus activated, inhibitory, and signal response domains and is activated by serine 477 and 479 phosphorylation (25). Although IRF7 is expressed at low levels in nonstimulated cells, IRF7 is critical for type I IFN expression, particularly in plasmacytoid dendritic cells (24,26,27). Toll-like receptor activation, LMP1 expression, viral infection, and other signals that activate IRF3 and induce IFN ␤ (IFN␤), can up-regulate IRF7 expression (18, 21-24, 28, 29). IRF7 can bind and localize to MyD88 until ligand-activated Toll-like receptors 7, 8, or 9 engage MyD88 and activate IRF7, which enters the nucleus and up-regulates IFN stimulated response elements (ISREs) to activate I...

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IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-κB activation

Cited by 51 publications

References 51 publications

TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1

TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1

NF-κB Activation Coordinated by IKKβ and IKKε Enables Latent Infection of Kaposi's Sarcoma-Associated Herpesvirus

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

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