STAP-2 negatively regulates both canonical and noncanonical NF-kappaB activation induced by Epstein-Barr virus-derived latent membrane protein 1.
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-alpha or IKK-beta and modulates NF-kappaB signaling in macrophages. In the present study, we found that ectopic expression of STAP-2 inhibited Epstein-Barr virus (EBV) LMP1-mediated NF-kappaB 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-kappaB 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.
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Osamu
O
Ikeda
Yuichi
Y
Sekine
Teruhito
T
Yasui
Kenji
K
Oritani
Kenji
K
Sugiyma
Ryuta
R
Muromoto
Norihiko
N
Ohbayashi
Akihiko
A
Yoshimura
Tadashi
T
Matsuda
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015850:Interleukin-6; D016328:NF-kappa B; D010750:Phosphoproteins; D012333:RNA, Messenger; C413897:STAP2 protein, human; D053199:TNF Receptor-Associated Death Domain Protein; D048008:TNF Receptor-Associated Factor 3; D014157:Transcription Factors; D014763:Viral Matrix Proteins