roles of the kinase tak1 in traf6-dependent signaling by cd40 and its oncogenic viral mimic, lmp1角色的激酶tak1 traf6-dependent cd40及其致癌病毒模拟信号,lmp1.pdfVIP

Roles of the Kinase TAK1 in TRAF6-Dependent Signaling by CD40 and Its Oncogenic Viral Mimic, LMP1 1 2,3 Kelly M. Arcipowski , Gail A. Bishop * 1 Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa, United States of America, 2 Interdisciplinary Graduate Program in Molecular and Cellular Biology, Departments of Microbiology and Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America, 3 Veterans Affairs Medical Center, Iowa City, Iowa, United States of America Abstract The Epstein-Barr virus (EBV)-encoded protein latent membrane protein 1 (LMP1) is essential for EBV-mediated B cell transformation and plays a critical role in the development of post-transplant B cell lymphomas. LMP1 also contributes to the exacerbation of autoimmune diseases such as systemic lupus erythematosus (SLE). LMP1 is a functional mimic of the tumor necrosis factor receptor (TNFR) superfamily member CD40, and relies on TNFR-associated factor (TRAF) adaptor proteins to mediate signaling. However, LMP1 activation signals to the B cell are amplified and sustained compared to CD40 signals. We previously demonstrated that LMP1 and CD40 use TRAF molecules differently. Although associating with CD40 and LMP1 via separate mechanisms, TRAF6 plays a significant role in signal transduction by both. It is unknown whether TRAF6 mediates CD40 versus LMP1 functions via distinct or shared pathways. In this study, we tested the hypothesis that TRAF6 uses the kinase TAK1 to trigger important signaling pathways following both CD40 and LMP1 stimulation. We determined that TAK1 was required for JNK activation and interleukin-6 (IL-6) production mediated by CD40 and LMP1, in both mouse and human B cells. Additionally, TRAF3