Regulation of B cell homeostasis and activation by the tumor suppressor gene <i>CYLD </i>

Hövelmeyer, Nadine; Wunderlich, Frank; Massoumi, Ramin; Jakobsen, Carl-Johan; Song, Jian; Wörns, Marcus A.; Merkwirth, Carsten; Kovalenko, Andrew; Aumailley, Monique; Strand, Dennis; Brüning, Jens C.; Galle, Peter R.; Wallach, David; Fässler, Reinhard; Waisman, Ari

doi:10.1084/jem.20070318

Cited by 93 publications

(115 citation statements)

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“…Jin and colleagues (29) found massive hyperplasia and expansion of marginal zone B cells in CYLD-deficient mice and increased responses of CYLD-deficient B cells in response to activation. Similar effects were caused by the expression of a truncated CYLD lacking exons 7 and 8 (30). However, in another study, CYLD deficiency did not affect peripheral B cell numbers, but increased NF-kB activation after stimulation (31).…”

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confidence: 67%

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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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“…In the resulting CD19Cre/A20 1A) (30). CYLD-deficient mice were also intercrossed with CD19cre mice to control for the heterozygous ablation of CD19 and the expression of the Cre recombinase.…”

Section: Loss Of Cyld Does Not Exacerbate the Defects In A20-deficienmentioning

confidence: 99%

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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“…NF-κB1 (p105/p50) and NF-κB2 (p100/p52) need to be processed to become active and translocate to the nucleus where they associate with RelA (p65), c-Rel and RelB in different hetero-and homodimers to form the transcriptionally active complex. 16 Mice deficient in RelB show reduced numbers of MZ B cells, 17 whereas mice lacking a negative regulator of NF-κB have more MZ B cells 18 similar to mice that lack the inhibitory p100 subunit of NF-κB2. 19 We therefore quantified the abundance of all NF-κB proteins in the cytosol and the nucleus by immunoblotting of subcellular fractions obtained from freshly isolated splenocytes.…”

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confidence: 99%

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

et al. 2015

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The endoplasmic reticulum (ER) serves as the major intracellular Ca 2+ store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca 2+ leak channel also implicated in the response against protein misfolding, thereby connecting the Ca 2+ store and protein-folding functions of the ER. We found that BI-1-deficient mice suffer from leukopenia and erythrocytosis, have an increased number of splenic marginal zone B cells and higher abundance and nuclear translocation of NF-κB (nuclear factor-κ light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca 2+ levels. When put into culture, purified knockout T cells and even more so B cells die spontaneously. This is preceded by increased activity of the mitochondrial initiator caspase-9 and correlated with a significant surge in mitochondrial Ca 2+ levels, suggesting an exhausted mitochondrial Ca 2+ buffer capacity as the underlying cause for cell death in vitro. In vivo, T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production are attenuated, corroborating the ex vivo results. These results suggest that BI-1 has a major role in the functioning of the adaptive immune system by regulating intracellular Ca 2+ homeostasis in lymphocytes. Cell Death and Differentiation (2016) 23, 358-368; doi:10.1038/cdd.2015; published online 16 October 2015The endoplasmic reticulum (ER) serves as the major intracellular calcium (Ca 2+ ) store, the release of which controls a vast array of cellular functions from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation. 1 Dysregulated release of ER Ca 2+ , in contrast, initiates programmed cell death by several mechanisms including mitochondrial Ca 2+ overload, depolarization, ATP loss and cytochrome c release. 2 Besides this, the ER also has a key role in the synthesis, folding and sorting of proteins destined for the secretory pathway. The deleterious consequences of an increase in unfolded proteins is called ER stress and can be antagonized by the unfolded protein response (UPR), a mechanism that coordinates a simultaneous increase in the ER folding capacity and a decrease in folding load. In the case of insufficient adaptation to ER stress, cells undergo apoptosis. 3 BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is an evolutionarily conserved protein that bridges both the Ca 2+ homeostasis and UPR functions of the ER. 4 BI-1 was first identified in a screen for human proteins capable of inhibiting BAX-mediated cell death in yeast. 5 In mammalian cells, BI-1's antiapoptotic function is most pronounced in paradigms of ER stress 6 and involves changes in the amount of Ca 2+ that can be released from intracellular stores. 6,7 BI-1 is a highly hydrophobic protein that forms a Ca 2+ pore responsible for its Ca 2+ leak properties 8 and is the founding member of a family of six proteins with similar properties. 9 The increase in the ER Ca 2+ lea...

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“…For example, impaired CYLD expression is associated with immune diseases like inflammatory bowel disease (13). However, a number of recent studies in different mice bearing obligatory null alleles demonstrated putative, essential, yet contrasting roles for CYLD in the regulation of adaptive and innate immune responses (14)(15)(16)(17)(18). A first report aimed to eliminate CYLD functions in the mouse through the germ-line removal of the ATGcontaining exon 2 from the murine Cyld locus (15).…”

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Thymocyte-Specific Truncation of the Deubiquitinating Domain of CYLD Impairs Positive Selection in a NF-κB Essential Modulator-Dependent Manner

Tsagaratou

Trompouki

Grammenoudi

et al. 2010

The Journal of Immunology

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The cylindromatosis tumor suppressor gene (Cyld) encodes a deubiquitinating enzyme (CYLD) with immunoregulatory function. In this study, we evaluated the role of Cyld in T cell ontogeny by generating a mouse (CyldΔ9) with a thymocyte-restricted Cyld mutation that causes a C-terminal truncation of the protein and reciprocates catalytically inactive human mutations. Mutant mice had dramatically reduced single positive thymocytes and a substantial loss of peripheral T cells. The analyses of polyclonal and TCR-restricted thymocyte populations possessing the mutation revealed a significant block in positive selection and an increased occurrence of apoptosis at the double-positive stage. Interestingly, in the context of MHC class I and II restricted TCR transgenes, lack of functional CYLD caused massive deletion of thymocytes that would have been positively selected, which is consistent with an impairment of positive selection. Biochemical analysis revealed that CyldΔ9 thymocytes exhibit abnormally elevated basal activity of NF-κB and JNK. Most importantly, inactivation of NF-κB essential modulator fully restored the NF-κB activity of CyldΔ9 thymocytes to physiologic levels and rescued their developmental and survival defect. This study identifies a fundamental role for functional CYLD in establishing the proper threshold of activation for thymocyte selection by a mechanism dependent on NF-κB essential modulator.

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Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD

Cited by 93 publications

References 31 publications

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

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

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

Thymocyte-Specific Truncation of the Deubiquitinating Domain of CYLD Impairs Positive Selection in a NF-κB Essential Modulator-Dependent Manner

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