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R-Ras2 is required for germinal center formation to aid B cells during energetically demanding processes

AuthorsMendoza, Pilar; Martínez-Martín, Nuria ; Bovolenta, Paola ; Reyes-Garau, Diana; Hernansanz-Agustín, Pablo; Delgado, Pilar ; Díaz-Muñoz, Manuel D.; Oeste, Clara L. ; Fernández-Pisonero, Isabel; Castellano, Esther; Martínez-Ruiz, Antonio ; Alonso-López, D.; Santos de Dios, Eugenio ; Bustelo, Xosé R. ; Kurosaki, Tomohiro; Alarcón, Balbino
Issue Date2018
PublisherAmerican Association for the Advancement of Science
CitationScience Signaling 11(532): eaal1506 (2018)
AbstractUpon antigen recognition within peripheral lymphoid organs, B cells interact with T cells and other immune cells to transiently form morphological structures called germinal centers (GCs), which are required for B cell clonal expansion, immunoglobulin class switching, and affinity maturation. This process, known as the GC response, is an energetically demanding process that requires the metabolic reprogramming of B cells. We showed that the Ras-related guanosine triphosphate hydrolase (GTPase) R-Ras2 (also known as TC21) plays an essential, nonredundant, and B cell–intrinsic role in the GC response. Both the conversion of B cells into GC B cells and their expansion were impaired in mice lacking R-Ras2, but not in those lacking a highly related R-Ras subfamily member or both the classic H-Ras and N-Ras GTPases. In the absence of R-Ras2, activated B cells did not exhibit increased oxidative phosphorylation or aerobic glycolysis. We showed that R-Ras2 was an effector of both the B cell receptor (BCR) and CD40 and that, in its absence, B cells exhibited impaired activation of the PI3K-Akt-mTORC1 pathway, reduced mitochondrial DNA replication, and decreased expression of genes involved in glucose metabolism. Because most human B cell lymphomas originate from GC B cells or B cells that have undergone the GC response, our data suggest that R-Ras2 may also regulate metabolism in B cell malignancies.
Identifiersdoi: 10.1126/scisignal.aal1506
e-issn: 1937-9145
issn: 1945-0877
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