The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells

Ubiquitination plays a central role in the regulation of various biological functions including immune responses. Ubiquitination is induced by a cascade of enzymatic reactions by E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase, and reversed by deubiquitinases. Depending on the enzymes, specific linkage types of ubiquitin chains are generated or hydrolyzed. Because different linkage types of ubiquitin chains control the fate of the substrate, understanding the regulatory mechanisms of ubiquitin enzymes is central. In this review, we highlight the most recent knowledge of ubiquitination in the immune signaling cascades including the T cell and B cell signaling cascades as well as the TNF signaling cascade regulated by various ubiquitin enzymes. Furthermore, we highlight the TRIM ubiquitin ligase family as one of the examples of critical E3 ubiquitin ligases in the regulation of immune responses.

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“…2012). CYLD-deficient mice display a markedly increased number of Tregs in the periphery, but not in the thymus.…”

Section: Ubiquitination In Various Immune Cell Signaling Cascadesmentioning

confidence: 99%

Ubiquitin enzymes in the regulation of immune responses

Ebner

Versteeg²,

Ikeda

2017

Critical Reviews in Biochemistry and Molecular Biology

106

123

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“…Studies using knockout mice revealed a role for CYLD in T cell biology (67)(68)(69)(70). In these studies, the absence of CYLD resulted in reduced accumulation of mature thymocytes and peripheral T lymphocytes.…”

Section: Discussionmentioning

confidence: 91%

“…In these studies, the absence of CYLD resulted in reduced accumulation of mature thymocytes and peripheral T lymphocytes. In addition, the differentiation of the CD4 ϩ T lymphocytes into T regulatory cell subsets was halted (67)(68)(69)(70). Cleavage of CYLD by the cellular paracaspase MALT1 was necessary for proper activation of CD4 ϩ T cells in response to T cell receptor stimulation (57).…”

Section: Discussionmentioning

confidence: 99%

Tumor Suppressor Cylindromatosis (CYLD) Controls HIV Transcription in an NF-κB-Dependent Manner

Manganaro

Pache

Herrmann

et al. 2014

J Virol

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Characterizing the cellular factors that play a role in the HIV replication cycle is fundamental to fully understanding mechanisms of viral replication and pathogenesis. Whole-genome small interfering RNA (siRNA) screens have identified positive and negative regulators of HIV replication, providing starting points for investigating new cellular factors. We report here that silencing of the deubiquitinase cylindromatosis protein (CYLD), increases HIV infection by enhancing HIV long terminal repeat (LTR)-driven transcription via the NF-B pathway. CYLD is highly expressed in CD4؉ T lymphocytes, monocyte-derived macrophages, and dendritic cells. We found that CYLD silencing increases HIV replication in T cell lines. We confirmed the positive role of CYLD silencing in HIV infection in primary human CD4 ؉ T cells, in which CYLD protein was partially processed upon activation. Lastly, Jurkat T cells latently infected with HIV (JLat cells) were more responsive to phorbol 12-myristate 13-acetate (PMA) reactivation in the absence of CYLD, indicating that CYLD activity could play a role in HIV reactivation from latency. In summary, we show that CYLD acts as a potent negative regulator of HIV mRNA expression by specifically inhibiting NF-Bdriven transcription. These findings suggest a function for this protein in modulating productive viral replication as well as in viral reactivation. IMPORTANCEHIV transcription is regulated by a number of host cell factors. Here we report that silencing of the lysine 63 deubiquitinase CYLD increases HIV transcription in an NF-B-dependent manner. We show that CYLD is expressed in HIV target cells and that its silencing increases HIV infection in transformed T cell lines as well as primary CD4 ؉ T cells. Similarly, reactivation of latent provirus was facilitated in the absence of CYLD. These data suggest that CYLD, which is highly expressed in CD4 ؉ T cells, can control HIV transcription in productive infection as well as during reactivation from latency.

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“…CYLD also limits tTreg generation due to antagonism of NFκB signaling [142]. Mice expressing a mutant CYLD that is incapable of binding the targets TRAF2 and NEMO displayed hyperactive T cell proliferation and activation accompanying poorly restrained NFκB activity.…”

Section: The Deubiquitinases: the Other Side Of The Storymentioning

confidence: 99%

“…As with CYLD deficiency, Treg frequencies in these mice were elevated in the absence of functional CYLD [140] – an observation perhaps expected due to the importance of both TGFβ and NFκB signaling in early tTreg development [143]. However, Tregs with inactive CYLD were less effective suppressors than their wild type counterparts [142], a potential example of the distinct consequences of robust NFκB activation for Treg development and Treg function. It was recently revealed that PKCθ, a facilitator of TCR/CD28-induced NFκB signaling, binds to CYLD in T cells antagonizing the DUB’s inhibition of NFκB and NFAT transactivation.…”

Section: The Deubiquitinases: the Other Side Of The Storymentioning

confidence: 99%

Ubiquitous points of control over regulatory T cells

Fan

Barbi

2014

J Mol Med

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Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins and processes including DNA repair, cell cycle progression, protein quality control and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. It is now clear that the activities of molecules and pathways central to immune regulation are also modified and regulated through ubiquitin. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on signaling pathways pertinent for these cells or through the direct, posttranslational regulation of Foxp3. In this review we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of biology of Tregs including their generation, function and phenotypic fidelity. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine-tuning of immune restraint.

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The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells

Cited by 34 publications

References 44 publications

Ubiquitin enzymes in the regulation of immune responses

Ubiquitin enzymes in the regulation of immune responses

Tumor Suppressor Cylindromatosis (CYLD) Controls HIV Transcription in an NF-κB-Dependent Manner

Ubiquitous points of control over regulatory T cells

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