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Mol. Cell. Biol. doi:10.1128/MCB.00194-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

STAP-2 negatively regulates both canonical and non-canonical NF-B activation induced by Epstein-Barr virus-derived LMP1

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

^* To whom correspondence should be addressed. Email: tmatsuda{at}pharm.hokudai.ac.jp.

	Abstract

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains 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-/, 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 SH-2-like domains, and these proteins interacted with each other in EBV-positive human B cells. We further found that STAP-2 regulated LMP1-mediated NF-B signaling through direct or indirect interactions with tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 3 and TNFR-associated death domain protein (TRADD). STAP-2 mRNA was induced by 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.