The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity

Kool, Mirjam; Loo, Geert; Waelput, Wim; Prijck, Sofie De; Muskens, Femke; Sze, Mozes; Praet, Jens Van; Branco-Madeira, Filipe; Janssens, Sophie; Reizis, Boris; Elewaut, Dirk; Beyaert, Rudi; Hammad, Hamida; Lambrecht, Bart N.

doi:10.1016/j.immuni.2011.05.013

Cited by 222 publications

(223 citation statements)

References 46 publications

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“…This provides a framework for understanding the role of A20 in suppressing B-cell lymphomas, which is suggested by human genetic studies (36,96,161). Other studies have found critical functions for A20 in dendritic cells (83,126), macrophages (167), and intestinal epithelial cells (265).…”

Section: Otu Familymentioning

confidence: 84%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

375

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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Section: Otu Familymentioning

confidence: 84%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

375

384

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“…The crosstalk between DCs and myeloid cells is likely mediated by FLT3L, given the key role of FLT3L in myeloid cell expansion (21,60), although this action does not appear to affect myeloid populations in the BM. Recently, expansion of myeloid populations and increases of serum FLT3L levels have been reported in mice with DC-selective deletion of A20, a negative regulator of NF-κB signaling (66,67). However, unlike DCs lacking TAK1, A20-deficient DCs show enhanced responses to CD40 and RANKmediated survival signals and trigger profound activation of T cells and B cells and development of autoimmunity (66,67).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, expansion of myeloid populations and increases of serum FLT3L levels have been reported in mice with DC-selective deletion of A20, a negative regulator of NF-κB signaling (66,67). However, unlike DCs lacking TAK1, A20-deficient DCs show enhanced responses to CD40 and RANKmediated survival signals and trigger profound activation of T cells and B cells and development of autoimmunity (66,67). Therefore, immune homeostasis under steady state is dependent upon molecular signals in DCs, especially a delicate threshold of NF-κB signaling.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Wang¹,

Huang²,

Vogel³

et al. 2012

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

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Homeostatic control of dendritic cell (DC) survival is crucial for adaptive immunity, but the molecular mechanism is not well defined. Moreover, how DCs influence immune homeostasis under steady state remains unclear. Combining DC-specific and -inducible deletion systems, we report that transforming growth factor betaactivated kinase 1 (TAK1) is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c + cells induced markedly elevated apoptosis, leading to the depletion of DC populations, especially the CD8 + and CD103 + DC subsets in lymphoid and nonlymphoid tissues, respectively. TAK1 also contributed to DC development by promoting the generation of DC precursors. Prosurvival signals from Toll-like receptors, CD40 and receptor activator of nuclear factor-κB (RANK) are integrated by TAK1 in DCs, which in turn mediated activation of downstream NF-κB and AKT-Foxo pathways and established a gene-expression program. TAK1 deficiency in DCs caused a myeloid proliferative disorder characterized by expansion of neutrophils and inflammatory monocytes, disrupted T-cell homeostasis, and prevented effective T-cell priming and generation of regulatory T cells. Moreover, TAK1 signaling in DCs was required to prevent myeloid proliferation even in the absence of lymphocytes, indicating a previously unappreciated regulatory mechanism of DC-mediated control of myeloid cell-dependent inflammation. Therefore, TAK1 orchestrates a prosurvival checkpoint in DCs that affects the homeostasis and function of the immune system. innate immunity | immune tolerance

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“…Lack of signal containment in A20-deficient mice results in severe inflammation and lethality that is triggered by MyD88-dependent TLR signaling initiated by the commensal flora (7,8). Cell type-specific deletion of A20 in immune cells and other tissues like intestinal epithelial cells and skin further confirmed its crucial role in the maintenance of tissue homeostasis and to prevent inflammatory diseases including autoimmunity (9)(10)(11)(12)(13)(14)(15). In B cells, loss of A20 causes hyperreactivity, general immune activation, and the production of autoantibodies (10,11,16).…”

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confidence: 90%

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

Chu

Soberon

Glockner

et al. 2012

The Journal of Immunology

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The ubiquitin-editing enzyme A20 (TNFAIP3) and the deubiquitinase CYLD are central negative regulators of NF-kappa B signaling. Both can act by removing nonproteolytic K63-linked polyubiquitin chains from an overlapping set of signaling molecules. In B cells, A20 deficiency results in hyperactivity, loss of immune homeostasis, inflammation, and autoimmunity. The reported consequences of CYLD deficiency are controversial, ranging from an absence of effects to dramatic B cell hyperplasia. These differences could be due to varying compensation for the loss of CYLD function by A20. Therefore, to explore potential overlapping physiological functions between A20 and CYLD, we generated and characterized A20/CYLD double-deficient B cells. Interestingly, the lack of both A20 and CYLD did not exacerbate the developmental defects and hyperresponsive activity of A20-deficient B cells. In addition, the extent of B cell activation after in vitro stimulation with anti-CD40, LPS, and CpG was comparable in B cells lacking A20/CYLD and A20 alone. However, in response to BCR cross-linking, we observed small but reproducible additive effects of the lack of A20 and CYLD. Taken together, our results demonstrate that A20 and CYLD do not share significant functions during B cell development and activation. The Journal of Immunology, 2012, 189: 4437-4443

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The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity

Cited by 222 publications

References 46 publications

Deubiquitylases From Genes to Organism

Deubiquitylases From Genes to Organism

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

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