The Deubiquitinase CYLD Targets Smad7 Protein to Regulate Transforming Growth Factor β (TGF-β) Signaling and the Development of Regulatory T Cells

Zhao, Yongge; Thornton, Angela M.; Kinney, Matthew C.; Chi, Aiping; Spinner, Jacob J.; Fuss, Ivan J.; Shevach, Ethan M.; Jain, Ashish

doi:10.1074/jbc.m111.292961

Cited by 71 publications

(61 citation statements)

References 35 publications

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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%

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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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Section: Discussionmentioning

confidence: 91%

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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“…The USP family member CYLD (cylindromatosis), plays a role in the generation of Tregs. In response to TGF-β signaling, K63-linked polyubiquitylation of Smad7 results in stabilized Smad7 which activates TAK1, increases binding of AP-1 to the foxp3 promoter, and increases Foxp3 transcription 122 . CYLD opposes this process by removing K63 chains on Smad7.…”

Section: Regulatory T Cells (Tregs)mentioning

confidence: 99%

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

Layman

Oliver

2016

The Journal of Immunology

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The human body is exposed to potentially pathogenic microorganisms at barrier sites such as the skin, lungs, and GI tract. To mount an effective response against these pathogens, the immune system must recruit the right cells with effector responses that are appropriate for the task at hand. Several types of CD4+ T cells can be recruited, including T helper cells known as Th1, Th2, and Th17, T follicular helper (Tfh) cells, and regulatory T cells (Tregs). These cells help to maintain normal immune homeostasis in the face of constantly changing microbes in the environment. As these cells differentiate from a common progenitor, the composition of their intracellular milieu of proteins changes to appropriately guide their effector function. One underappreciated process that impacts both levels and functions of effector fate-determining factors is ubiquitylation. This review will detail our current understanding of how ubiquitylation regulates CD4 T cell effector identity and function.

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“…The crystal structure of the USP domain and results from in vitro deubiquitylation assays have demonstrated that CYLD has lysine-63 (K63)-linked polyubiquitin-chain-specific endodeubiquitylase activity (Komander et al, 2008(Komander et al, , 2009Sato et al, 2015). A series of studies has found that CYLD regulates multiple signaling pathways, including nuclear factor-кB (NF-кB), Wnt/β-catenin, c-Jun Nterminal kinase (JNK), p38 mitogen-activated protein kinase ( p38 MAPK), transforming growth factor-β (TGF-β), Hippo and Notch signaling Lim et al, 2012;Massoumi, 2010;Rajan et al, 2014;Welte et al, 2014;Zhao et al, 2011) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions

Yang

Zhou

2016

Journal of Cell Science

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Microtubules are dynamic structures that are crucially involved in a variety of cellular activities. The dynamic properties and functions of microtubules are regulated by various factors, such as tubulin isotype composition and microtubule-binding proteins. Initially identified as a deubiquitylase with tumor-suppressing functions, the protein cylindromatosis (CYLD) has recently been revealed to interact with microtubules, modulate microtubule dynamics, and participate in the regulation of cell migration, cell cycle progression, chemotherapeutic drug sensitivity and ciliogenesis. These findings have greatly enriched our understanding of the roles of CYLD in physiological and pathological conditions. Here, we focus on recent literature that shows how CYLD impacts on microtubule properties and functions in various biological processes, and discuss the challenges we face when interpreting results obtained from different experimental systems.

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The Deubiquitinase CYLD Targets Smad7 Protein to Regulate Transforming Growth Factor β (TGF-β) Signaling and the Development of Regulatory T Cells

Cited by 71 publications

References 35 publications

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

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

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions

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