Site-specific Monoubiquitination of IκB Kinase IKKβ Regulates Its Phosphorylation and Persistent Activation

Carter, Robert S.; Pennington, Kevin N.; Arrate, Pia; Oltz, Eugene M.; Ballard, Dean W.

doi:10.1074/jbc.m508656200

Cited by 34 publications

(37 citation statements)

References 32 publications

(83 reference statements)

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“…Notably, Mdm2 has been previously shown to lead to mono-and polyubiquitination of substrate proteins (34). Monoubiquitination is suggested to be important for regulating the intracellular trafficking of proteins (35,36) as well as for persistent activity of some signaling kinases (37). Although the exact mechanism is not known, our data indicate that ubiquitination of ␤-arrestin1 is induced upon IGF-1R stimulation and this is important for trafficking as well as the prolonged downstream ERK activation.…”

Section: Discussionmentioning

confidence: 51%

β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression

Girnita

Shenoy

Sehat

et al. 2007

Journal of Biological Chemistry

119

141

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␤-Arrestin1, which regulates many aspects of seven transmembrane receptor (7TMR) biology, has also been shown to serve as an adaptor, which brings Mdm2, an E3 ubiquitin ligase to the insulin-like growth factor-1 receptor (IGF-1R), leading to its proteasome-dependent destruction. Here we demonstrate that IGF-1R stimulation also leads to ubiquitination of ␤-arrestin1, which regulates vesicular trafficking and activation of ERK1/2. This ␤-arrestin1-dependent ERK activity can occur even when the classical tyrosine kinase signaling is impaired. siRNA-mediated suppression of ␤-arrestin1 in human melanoma cells ablates IGF-1-stimulated ERK and prolongs the G 1 phase of the cell cycle. These data suggest that ␤-arrestin-dependent ERK signaling by the IGF-1R regulates cell cycle progression and may thus be an important regulator of the growth of normal and malignant cells.

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Section: Discussionmentioning

confidence: 51%

β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression

Girnita

Shenoy

Sehat

et al. 2007

Journal of Biological Chemistry

119

141

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“…9). In support of this possibility, the activity of IKK␤, a kinase in the NFB pathways, has been shown to be regulated by monoubiquitination (9). Direct identification of ubiquitination sites by mass spectrometry remains technically challenging, especially for higher eukaryotes where knock-in mutation is not nearly as feasible as in yeast cells.…”

Section: Discussionmentioning

confidence: 99%

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

100

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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“…In this vein, it is interesting that Tax is extensively modified posttranslationally by phosphorylation, ubiquitination, and sumoylation (6,17,23). K63 polyubiquitination of IKK␥ and monoubiquitination of IKK␤ are highly induced by Tax (2). Recent data have also suggested that UBC13/UBE2N, an E2-conjugating enzyme involved in IKK activation, can associate with both Tax and IKK␥ and is critical for their K63 polyubiquitination and Tax-mediated IKK activation (27), a conclusion further sup- ported by a cell-free IKK activation system for Tax elegantly established by Shibata et al (28).…”

Section: Discussionmentioning

confidence: 99%

HTLV-1 Tax-Induced Rapid Senescence Is Driven by the Transcriptional Activity of NF-κB and Depends on Chronically Activated IKKα and p65/RelA

Zhi

DeBiaso

et al. 2012

J Virol

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The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-κB pathways and is thought to promote cell proliferation and transformation via NF-κB activation. We showed recently that hyperactivation of NF-κB by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-κB activation by expression of I-κBα superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescence (Tax-IRS). Here we demonstrate that Tax-IRS is driven by the transcriptional activity of NF-κB. Knockdown of IKKγ, the primary Tax target, by shRNAs abrogated Tax-mediated activation of both classical and alternative NF-κB pathways and rendered knockdown cells resistant to Tax-IRS. Consistent with a critical role of IKKα in the transcriptional activity of NF-κB, IKKα deficiency drastically decreased NF-κB trans -activation by Tax, although it only modestly reduced Tax-mediated I-κBα degradation and NF-κB nuclear localization. In contrast, although IKKβ knockdown attenuated Tax-induced NF-κB transcriptional activation, the residual NF-κB activation in IKKβ-deficient cells was sufficient to trigger Tax-IRS. Importantly, the phenotypes of NIK and TAK1 knockdown were similar to those of IKKα and IKKβ knockdown, respectively. Finally, double knockdown of RelB and p100 had a minor effect on senescence induction by Tax. These data suggest that Tax, through its interaction with IKKγ, helps recruit NIK and TAK1 for IKKα and IKKβ activation, respectively. In the presence of Tax, the delineation between the classical and alternative NF-κB pathways becomes obscured. The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-κB, which depends on activated IKKα and p65/RelA.

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Site-specific Monoubiquitination of IκB Kinase IKKβ Regulates Its Phosphorylation and Persistent Activation

Cited by 34 publications

References 32 publications

β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression

β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression

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

HTLV-1 Tax-Induced Rapid Senescence Is Driven by the Transcriptional Activity of NF-κB and Depends on Chronically Activated IKKα and p65/RelA

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