Role of Rab7 in activating NF-kB in B cells to mediate class-switching and plasma cell survival in antibody and autoantibody responses and to promote B cell lymphomagenesis

Abstract

Abstract NF-kappaB activation mediates B cell class-switching to generate IgG, IgA and IgE as well as survival of plasma cells, as differentiated from B cells to secrete antibodies at a high rate. Here we have identified a B cell-intrinsic role of Rab7, a small GTPase located in endosomes, in activating NF-kappaB for class-switching and plasma cell survival. Mice that are deficient in Rab7 specifically in B cells or treated with CID 1067700, a Rab7-specific small molecule inhibitor, cannot mount T-independent or T-dependent switched antibody responses, despite normal B cell proliferation/survival and T cell/myeloid cells functions. Rab7 co-localizes, on endosomes, with the CD40 receptor that is internalized upon engagement and directly interacts with TRAF6, an adaptor of CD40 and TLR signaling for NF-kB activation, thereby forming complexes that transduce signals. Disruption of such complexes by CID 1067700 hampers NF-kappaB activation in normal B cells and abrogates NF-kappaB dysregulation in lupus B cells and B lymphoma cell lines, in which Rab7 is upregulated. Treatment with CID 1067700 reduces pathogenic IgG autoantibody responses in murine lupus models, leading to life-span extension, and prevents tumorigenesis in nude mice transplanted with B lymphoma cells. These, together with the rescue of class-switching/plasma cell survival in normal B cells and proliferation/survival of B lymphoma cells by enforced NF-kappaB activation, indicate that Rab7 plays an important role in NF-kappaB activation to mediate B cell differentiation and dysregulation and is a potential therapeutic target in lupus and B cell lymphomagenesis. Supported by NIH grants AI 079705, AI 105813/105813S1 (to P. C.) and AI 124172 (to Z. X.).