The Role of Ubiquitin in NF-κB Regulatory Pathways

Skaug, Brian; Jiang, Xiaomo; Chen, Zhijian J.

doi:10.1146/annurev.biochem.78.070907.102750

Cited by 439 publications

(422 citation statements)

References 150 publications

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“…Various stimuli activate the classical NF-κB pathway. Agonist stimulation induces adapter recruitment to the cognate receptor, which then activates the IKK complex by a process that involves linear and K63-linked ubiquitination, as well as phosphorylation (reviewed in Skaug et al [101], Vallabhapurapu and Karin [102]). IKK phosphorylates two N-terminal residues in IκBα, creating a binding site for the SCF βTrCP ubiquitin E3 ligase complex, which attaches K48-linked ubiquitin chains to two adjacent lysine residues, targeting IκBα for proteasomal degradation.…”

Section: Regulation Of Tpl-2 Signaling By Nf-κb1 P105mentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

130

157

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The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

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Section: Regulation Of Tpl-2 Signaling By Nf-κb1 P105mentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

130

157

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“…However, the source of the dichotomy in mutated versus unmutated CLL cells on CD40/TLR9 triggering might well lie in differential NF-kB signaling mediated through upstream regulators, such as cIAP1/2, A20, NIK and TRAF family members. The complex interplay between these signaling modulators is currently the subject of intense scrutiny (Skaug et al, 2009;Silke and Brink, 2010). In addition, combined CD40/ TRL9 triggering induces proliferation in unmutated CLL cells, suggesting that these signaling pathways can also interfere or even replace signals that are presumed to initiate from the B-cell receptor.…”

Section: Discussionmentioning

confidence: 99%

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

et al. 2010

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Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavychain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-jB (NF-jB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X L levels, respectively. A dichotomy in NF-jB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X L levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X L and remained chemoresistant. The pivotal contribution of Bcl-X L to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X L levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-jB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X L levels.

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“…The synthesis of polyubiquitin chains linked by linear, K48, and K63 is critical for the activation of NF-kB and MAPKs (1)(2)(3). In unstimulated cells, NF-kB is sequestered in the cytoplasm by association with an inhibitory protein, IkBa.…”

mentioning

confidence: 99%

“…Alternatively, conjugation of linear polyubiquitin chains to NEMO by a linear ubiquitin chain assembly complex (LUBAC), comprised of heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL-1), HOIL-1-interacting protein, and shankassociated RH domain-interacting protein (SHARPIN), is responsible for activation of NF-kB (4,5). Furthermore, K63-linked polyubiquitin chains are also reported to be essential for the activation of NF-kB and MAPKs (3,6,7). In response to TLR stimulation, TNFR-associated factor (TRAF)6 has been shown to catalyze K63-linked polyubiquitination by acting as an E3 ubiquitin ligase.…”

mentioning

confidence: 99%

“…An E2 ubiquitin ligase complex comprised of UBC13 and Uev1A generates K63-linked polyubiquitin chains, which are anchored to TRAF6 or act as an unanchored signaling mediator (8)(9)(10). Downstream of TRAF6 and UBC13, TGF-b-activated kinase 1 (TAK1) is known to be activated by these stimuli and to phosphorylate IKKb and MAPK kinase 6 for activation (3). Although K63-linked polyubiquitination has been implicated in TNF signaling, mutation of ubiquitin K63 to R failed to impair IKK activation by TNF (11).…”

mentioning

confidence: 99%

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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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The Role of Ubiquitin in NF-κB Regulatory Pathways

Cited by 439 publications

References 150 publications

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

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

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