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J. Biol. Chem., Vol. 283, Issue 18, 12546-12554, May 2, 2008

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

Tomoaki Koga, Jae Hyang Lim, Hirofumi Jono, Un Hwan Ha, Haidong Xu, Hajime Ishinaga, Saori Morino, Xiangbin Xu, Chen Yan^¶1, Hirofumi Kai, and Jian-Dong Li²

From the Department of Microbiology and Immunology and ^¶Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York 14642 and the Department of Molecular Medicine, Kumamoto University, Kumamoto 862-0973, Japan

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 Ca²⁺-calcineurin and transforming growth factor-β-activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase (MKK) 3/6-p38/β-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-p38/β 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.

Received for publication, December 26, 2007 , and in revised form, February 20, 2008.

^* This work was supported by National Institutes of Health Grants DC005843 and DC004562 (to J. D. L.) and P01 HL077789 and RO1 HL088400 (to C. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of American Heart Association Established Investigator Award 0740021 N.

² To whom correspondence should be addressed: Box 672, University of Rochester Medical Center, 601 Elmwood Ave., Rochester NY, 14642. Tel.: 585-275-7195; Fax: 585-276-2231; E-mail: Jian-Dong_Li{at}URMC.Rochester.edu.

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