Tumor suppressor cylindromatosis acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling.
Gram-positive bacterium Streptococcus pneumoniae is an important human pathogen that colonizes the upper respiratory tract and is also the major cause of morbidity and mortality worldwide. S. pneumoniae causes invasive diseases such as pneumonia, meningitis, and otitis media. Despite the importance of pneumococcal diseases, little is known about the molecular mechanisms by which S. pneumoniae-induced inflammation is regulated, especially the negative regulatory mechanisms. Here we show that S. pneumoniae activates nuclear factor of activated T cells (NFAT) signaling pathway and the subsequent up-regulation of inflammatory mediators via a key pneumococcal virulence factor, pneumolysin. We also demonstrate that S. pneumoniae activates NFAT transcription factor independently of Toll-like receptors 2 and 4. Moreover, S. pneumoniae induces NFAT activation via both Ca(2+)-calcineurin and transforming growth factor-beta-activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase (MKK) 3/6-p38alpha/beta-dependent signaling pathways. Interestingly, we found for the first time that tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for S. pneumoniae-induced NFAT signaling pathway via a deubiquitination-dependent mechanism. Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p38alpha/beta pathway. Our studies thus bring new insights into the molecular pathogenesis of S. pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling, thereby opening up new therapeutic targets for these diseases.
Koga
Tomoaki
T
Department of Microbiology and Immunology and Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York 14642, USA.
Lim
Jae Hyang
JH
Jono
Hirofumi
H
Ha
Un Hwan
UH
Xu
Haidong
H
Ishinaga
Hajime
H
Morino
Saori
S
Xu
Xiangbin
X
Yan
Chen
C
Kai
Hirofumi
H
Li
Jian-Dong
JD
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000502:physiology*; D013301:Streptolysins / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D001426:Bacterial Proteins; D019703:Calcineurin; D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D018836:Inflammation Mediators; D048371:MAP Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D050778:NFATC Transcription Factors; D013301:Streptolysins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C032290:plY protein, Streptococcus pneumoniae; C409984:CYLD protein, human; C511601:CYLD protein, mouse