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Molecular and Cellular Biology, August 2008, p. 5027-5042, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00194-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

STAP-2 Negatively Regulates both Canonical and Noncanonical NF-B Activation Induced by Epstein-Barr Virus-Derived Latent Membrane Protein 1

Osamu Ikeda,^1, Yuichi Sekine,^1, Teruhito Yasui,² Kenji Oritani,³ Kenji Sugiyma,⁴ Ryuta Muromoto,¹ Norihiko Ohbayashi,¹ Akihiko Yoshimura,⁵ and Tadashi Matsuda^1*

Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan,¹ Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,² Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan,³ Nippon Boehringer Ingelheim Co., Ltd., Kawanishi Pharma Research Institute, 3-10-1 Yato, Kawanishi, Hyogo 666-0193, Japan,⁴ Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan⁵

Received 7 February 2008/ Returned for modification 13 March 2008/ Accepted 9 June 2008

The signal-transducing adaptor protein 2 (STAP-2) is a recently identified adaptor protein that contains a pleckstrin homology (PH) and Src homology 2 (SH2)-like domains, as well as a proline-rich domain in its C-terminal region. In previous studies, we demonstrated that STAP-2 binds to MyD88 and IKK- or IKK-β and modulates NF-B signaling in macrophages. In the present study, we found that ectopic expression of STAP-2 inhibited Epstein-Barr virus (EBV) LMP1-mediated NF-B signaling and interleukin-6 expression. Indeed, STAP-2 associated with LMP1 through its PH and SH2-like domains, and these proteins interacted with each other in EBV-positive human B cells. We found, furthermore, that STAP-2 regulated LMP1-mediated NF-B signaling through direct or indirect interactions with the tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) and TNFR-associated death domain (TRADD) proteins. STAP-2 mRNA was induced by the expression of LMP1 in human B cells. Furthermore, transient expression of STAP-2 in EBV-positive human B cells decreased cell growth. Finally, STAP-2 knockout mouse embryonic fibroblasts showed enhanced LMP1-induced cell growth. These results suggest that STAP-2 acts as an endogenous negative regulator of EBV LMP1-mediated signaling through TRAF3 and TRADD.

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* Corresponding author. Mailing address: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan. Phone: 81-11-706-3243. Fax: 81-11-706-4990. E-mail: tmatsuda{at}pharm.hokudai.ac.jp

Published ahead of print on 23 June 2008.

These authors contributed equally to this work.

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Molecular and Cellular Biology, August 2008, p. 5027-5042, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00194-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.