Rhbdf1 is a novel target of TRAF3 inactivation in B lymphocytes

Abstract

Abstract TRAF3 is a new tumor suppressor gene in B lymphocytes. Deletions and mutations of TRAF3 were detected in human non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). We previously reported that specific deletion of TRAF3 in B lymphocytes causes prolonged survival of mature B cells, which eventually leads to B lymphoma development in mice. Here we identified Rhbdf1, a 7-transmembrane domain protein implicated in the trafficking of ER proteins, as a novel target of TRAF3 inactivation in B cells. Rhbdf1 expression was strikingly up-regulated in TRAF3-deficient premalignant B cells, B lymphomas and human MM at both the mRNA and protein levels. Normal physiological stimuli such as BAFF, CD40 or BCR could not induce the expression of Rhbdf1 in B cells regardless of the presence of TRAF3, suggesting that Rhbdf1 is specifically and aberrantly induced by TRAF3 inactivation in B cells. Biochemical fractionation studies revealed that Rhbdf1 was mainly localized at the ER in mouse splenic B cells and human MM. Interestingly, lentiviral shRNA vector-mediated knockdown of Rhbdf1 induced apoptosis and inhibited proliferation in human MM cells with TRAF3 deletions or mutations. Furthermore, bortezomib, an effective clinical drug for MM, drastically decreased Rhbdf1 protein levels in both TRAF3-deficient mouse B lymphoma and human MM. Taken together, our findings suggest that Rhbdf1 is a novel target of TRAF3 inactivation in B cells and may contribute to oncogenic B cell survival.