sharpin negatively associates with traf2-mediated nfκb activationsharpin负面关联与traf2-mediated nfκb激活.pdfVIP

SHARPIN Negatively Associates with TRAF2-Mediated NFkB Activation Yanhua Liang* Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, United States of America Abstract NFkB is an inducible transcriptional factor controlled by two principal signaling cascades and plays pivotal roles in diverse physiological processes including inflammation, apoptosis, oncogenesis, immunity, and development. Activation of NFkB signaling was detected in skin of SHAPRIN-deficient mice and can be diminished by an NFkB inhibitor. However, in vitro studies demonstrated that SHARPIN activates NFkB signaling by forming a linear ubiquitin chain assembly complex with RNF31 (HOIP) and RBCK1 (HOIL1). The inconsistency between in vivo and in vitro findings about SHARPIN’s function on NFkB activation could be partially due to SHARPIN’s potential interactions with downstream molecules of NFkB pathway. In this study, 17 anti-flag immunoprecipitated proteins, including TRAF2, were identified by mass spectrum analysis among Sharpin-Flag transfected mouse fibroblasts, B lymphocytes, and BALB/c LN stroma 12 cells suggesting their interaction with SHARPIN. Interaction between SHARPIN and TRAF2 confirmed previous yeast two hybridization reports that SHARPIN was one TRAF2’s partners. Furthermore, luciferase-based NFkB reporter assays demonstrated that SHARPIN negatively associates with NFkB activation, which can be partly compensated by over-expression of TRAF2. These data suggested that other than activating NFkB signaling by forming ubiquitin ligase complex with RNF31 and RBCK1, SHARPIN may also negatively associate with NFkB activation via interactions with other NFkB members, such as TRAF2. Citation: Liang Y (2011) SHARPIN Negatively Associates with TRAF2-Mediated NFkB Activation. PLoS ONE 6(7): e21696. doi:10.1371/journal.pone.0021696 Editor: Ant