Tumor Suppressor Cylindromatosis Acts as a Negative Regulator for Streptococcus pneumoniae-induced NFAT Signaling

Koga, Tomoaki; Lim, Jae Hyang; Jono, Hirofumi; Ha, Un-Hwan; Xu, Haidong; Ishinaga, Hajime; Morino, Saori; Xu, Xiangbin; Yan, Chen; Kai, Hirofumi; Li, Jiandong

doi:10.1074/jbc.m710518200

Cited by 48 publications

(39 citation statements)

References 44 publications

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“…It is worthy to note that the NFAT, NF-kB, and STAT3 pathways shown in this study to be regulated by RCAN1 are universally important during respiratory tract infections and have been extensively studied during Pneumococcus infection (64)(65)(66). Thus, it is likely that the phenotype observed in RCAN1-deficient animals may not be specific to P. aeruginosa infection.…”

Section: Discussionmentioning

confidence: 92%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.

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Section: Discussionmentioning

confidence: 92%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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“…These include activation of immune and inflammatory cells via interaction of pneumolysin with Toll-like receptor 4 [3], as well as by induction of Ca 2+ influx, particularly into phagocytes and epithelial cells, as a consequence of sublytic action of the toxin [4,5]. In both cases, this results in activation of intracellular signalling cascades, which trigger the synthesis of a range of pro-inflammatory neutrophil-and monocyte/macrophage-activating chemokines/cytokines [6][7][8].…”

mentioning

confidence: 99%

Pneumolysin induces release of matrix metalloproteinase-8 and -9 from human neutrophils

Cockeran¹,

Mitchell²,

Feldman³

2009

Eur Respir J

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The research question addressed in the current study was: does the pneumococcal pore-forming toxin, pneumolysin, mobilise matrix metalloproteinase (MMP) -8 and -9 from isolated human blood neutrophils at sublytic concentrations of 5, 10 and 20 ng?mL -1 ?MMPs were measured in the supernatants of unstimulated neutrophils and of cells exposed to pneumolysin and the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (f-MLP; 0.1 mM), individually and in combination, using ELISA procedures, and alterations in cytosolic Ca 2+ concentrations were monitored using a fura-2 acetoxymethyl ester (fura-2/AM)-based spectrofluorimetric method. Treatment of neutrophils with pneumolysin alone caused dose-related release of both MMPs, whereas f-MLP caused modest increases; the combination of both activators was, however, most effective. Pneumolysin/f-MLP-activated release of the MMPs from the cells was paralleled by increases in cytosolic Ca 2+ .Exposure of human neutrophils to pneumolysin is accompanied by mobilisation of MMPs, which is potentiated by f-MLP. If operative in vivo, pneumolysin-mediated release of MMPs from neutrophils and other cell types may contribute to the pathogenesis of severe pneumococcal disease.

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“…Previous studies using murine systems or immortalized human T cells suggested that CYLD might undergo proteolytic cleavage upon activation (25,26,57). Since productive HIV infection requires T cell activation, we tested whether CYLD was cleaved in primary human CD4 ϩ T cells.…”

Section: Cyld Is Highly Expressed In Primary Cd4mentioning

confidence: 99%

“…Several molecules regulating this pathway (e.g., NEMO, TRAF2, TAK1, and TRAF6) are substrates of CYLD (7,8,14,23,24). Moreover, CYLD itself has been proposed to act as a negative regulator of the NFAT pathway (25,26).…”

mentioning

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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Tumor Suppressor Cylindromatosis Acts as a Negative Regulator for Streptococcus pneumoniae-induced NFAT Signaling

Cited by 48 publications

References 44 publications

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Pneumolysin induces release of matrix metalloproteinase-8 and -9 from human neutrophils

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

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