IκBα Ubiquitination Is Catalyzed by an SCF-like Complex Containing Skp1, Cullin-1, and Two F-Box/WD40-Repeat Proteins, βTrCP1 and βTrCP2

Suzuki, Hiroshi; Chiba, Tomoki; Kobayashi, Masato; Takeuchi, Masahiro; Suzuki, Toshiaki; Ichiyama, Arata; Ikenoue, Tsuneo; Omata, Masao; Furuichi, Kiyoshi; Tanaka, Keiji

doi:10.1006/bbrc.1999.0289

Cited by 113 publications

(63 citation statements)

References 29 publications

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“…This motif is not found in IRF-3. SCF ␤TrCP2/Fbw1B contributes also to I B␣ ubiquitination (62), whereas SCF Skp2 ubiquitinates various cell cycle regulators including p27 Kip1 (23), p21 Cip1 (63), and p130 (64). SCF hCDC4/Fbw7 was shown to target cyclin E (65).…”

Section: Discussionmentioning

confidence: 99%

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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Activation of the innate arm of the immune system following pathogen infection relies on the recruitment of latent transcription factors involved in the induction of a subset of genes responsible for viral clearance. One of these transcription factors, IFN regulatory factor 3 (IRF-3), is targeted for proteosomal degradation following virus infection. However, the molecular mechanisms involved in this process are still unknown. In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection. Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3. Inactivation of NEDD8-activating E1 enzyme also results in stabilization of IRF-3 suggesting the NEDDylation also plays a role in IRF-3 degradation following Sendai virus infection. In agreement with this observation, IRF-3 is recruited to Cullin1 following virus infection and overexpression of a dominant-negative mutant of Cullin1 significantly inhibits the degradation of IRF-3 observed in infected cells. We also asked whether the C-terminal cluster of phosphoacceptor sites of IRF-3 could serve as a destabilization signal and we therefore measured the half-life of C-terminal phosphomimetic IRF-3 mutants. Interestingly, we found them to be short-lived in contrast to wild-type IRF-3. In addition, no degradation of IRF-3 was observed in TBK1−/− mouse embryonic fibroblasts. All together, these data demonstrate that virus infection stimulates a host cell signaling pathway that modulates the expression level of IRF-3 through its C-terminal phosphorylation by the IκB kinase-related kinases followed by its polyubiquitination, which is mediated in part by a Cullin-based ubiquitin ligase.

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Section: Discussionmentioning

confidence: 99%

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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“…Phosphorylation of the conserved destruction box serine residues (DSGXXS) in IkB proteins induces recognition by bTrCP, followed by K48-linked polyubiquitination by the Skp1-CulinRoc1/Rbx1/Hrt-1-F-box (SCF or SCRF) family of E3 ligases (Yaron et al 1998;Fuchs et al 1999;Kroll et al 1999;Spencer et al 1999;Suzuki et al 1999;Winston et al 1999;Wu and Ghosh 1999) coordinately with the E2 UbcH5 (Yaron et al 1998;Spencer et al 1999). …”

Section: Bcl-3-a Multipurpose Proteinmentioning

confidence: 99%

NF-κB, the first quarter-century: remarkable progress and outstanding questions

Hayden¹,

Ghosh²

2012

Genes Dev.

1,471

1,576

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The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.

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“…This SCF complex attaches ubiquitin, a small protein that marks other proteins for degradation by the proteasome system, to pI␤␣. Ubiquitinated pI␤␣ is then destroyed in the proteasome, and NF-␤ is activated (Yaron et al, 1998;Suzuki et al, 1999).…”

Section: Post-translational Regulation Of Ja Responses In Arabidoipsimentioning

confidence: 99%

The Jasmonate Signal Pathway

2002

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IκBα Ubiquitination Is Catalyzed by an SCF-like Complex Containing Skp1, Cullin-1, and Two F-Box/WD40-Repeat Proteins, βTrCP1 and βTrCP2

Cited by 113 publications

References 29 publications

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

NF-κB, the first quarter-century: remarkable progress and outstanding questions

The Jasmonate Signal Pathway

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