Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling

Yamamoto, Masahiro; Okamoto, Tomoyoshi; Takeda, Kiyoshi; Sato, Shintaro; Sanjo, Hideki; Uematsu, Satoshi; Saitoh, Tatsuya; Yamamoto, Naoki; Sakurai, Hiroaki; Ishii, Ken J.; Shoji, Yasuhiro; Kawai, Taro; Matsuura, Yoshiharu; Takeuchi, Osamu; Akira, Shizuo

doi:10.1038/ni1367

Cited by 245 publications

(295 citation statements)

References 57 publications

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“…IkBa degradation in response to LPS is also impaired in macrophages and splenocytes from Ubc13 +/-mice [43]. In contrast, Yamamoto et al revealed that Ubc13-deficient murine embryonic fibroblasts show normal activation of NF-kB in response to IL-1, whereas JNK activation is impaired [44]. Furthermore, TRAF6 poly-ubiquitination and TAK1 activation are normal in Ubc13-deficient cells; however, IKKg poly-ubiquitination upon IL-1 stim- Here IRAK-1 is K63-polyubiquitinated by Pellino, which is itself phosphorylated by IRAK-1.…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 98%

“…65,2008 Review Article 2967 ulation is impaired [44]. As UbcH7 is also known to mediate K63-linked poly-ubiquitination of TRAF6 [45], there might be redundancy for TRAF6 autoubiquitination, but not for IKKg poly-ubiquitination by TRAF6.…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

“…Furthermore, siRNA directed against either Ubc13 or Uev1A abolishes TRAF2-mediated signaling to NF-kB [46]. In contrast, Yamamoto et al demonstrated that Ubc13-deficient murine embryonic fibroblasts show normal activation of NF-kB and JNK in response to TNF [44]. The TAK1/TAB1/TAB2/TAB3 complex is also implicated in TNF signaling.…”

Section: Verstrepen Et Almentioning

confidence: 99%

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TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

398

297

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Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

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Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 98%

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

See 1 more Smart Citation

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

398

297

View full text Add to dashboard Cite

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“…NEMO also has the potential to bind K63-linked polyubiquitin chains, but the affinity of NEMO for linear polyubiquitin chains seems to be even greater than for K63-linked ubiquitin chains (20,21). It was shown that TAK1 and UBC13 are essential for the responses of macrophages and B cells to TLR and Ag receptor stimulation (22)(23)(24), leading to the activation of Ag-specific immune responses. Nevertheless, mouse embryonic fibroblasts lacking TAB2 showed normal NF-kB activation in response to TNF and IL-1b (24,25).…”

mentioning

confidence: 99%

Essential Roles of K63-Linked Polyubiquitin-Binding Proteins TAB2 and TAB3 in B Cell Activation via MAPKs

Ori

Kato

Sanjo

et al. 2013

The Journal of Immunology

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Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β–activated kinase 1 (TAK1)–binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis.

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“…37 In addition, IKKγ has been shown to control the activation of JNK and p38 MAPK by cooperating with Ubc13 E2 ubiqutin-conjugating enzyme. 38 JNK and p38 MAPK are well-known cytokineresponsive MAPKs and are coordinatively activated with NF-κB in response to a wide range of stimuli. Of note, JNK and p38 MAPK are also known to regulate Fra-1, which Chang et al 35 have shown is dysregulated in IKKγ-DN-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

et al. 2014

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IκB kinase β (IKKβ) is a catalytic subunit of the IKK complex, which activates nuclear factor-κB (NF-κB). Although its role in osteoclastogenesis is well established, the role of IKKβ in bone formation is poorly understood. Here, we report that conditional knockout of Ikkβ in limb bud mesenchymal cells results in the upregulation of monocyte chemoattractant protein-5 (MCP-5) in the perichondrium, which in turn inhibits the growth of longitudinal bone by compromising chondrocyte hypertrophy and increasing the apoptosis of chondrocytes within the growth plate. Contrary to expectations, IKKβ in cells of chondrocyte or osteoblast lineage was dispensable for bone growth. On the other hand, ex vivo experiments confirmed the role of MCP-5 in the growth of longitudinal bone. Furthermore, an in vitro study demonstrated that the action of IKKβ on MCP-5 is cell autonomous. Collectively, our results provide evidence for a previously unrecognized role of IKKβ in the regulation of the growth plate that is mediated through stimulation-independent downregulation of MCP-5 in the perichondrium.

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Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling

Cited by 245 publications

References 57 publications

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Essential Roles of K63-Linked Polyubiquitin-Binding Proteins TAB2 and TAB3 in B Cell Activation via MAPKs

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

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