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Sci Signal. 2018 May 29;11(532). pii: eaal1506. doi: 10.1126/scisignal.aal1506.

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

Author information

1
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
2
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. balarcon@cbm.csic.es nmartinez@cbm.csic.es.
3
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
4
INSERM UMR1043/CNRS UMR5282, Centre Hospitalier Universitaire (CHU) Purpan, BP3028, 31024 Toulouse, France.
5
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cancer, and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, Campus Unamuno s/n, 37007 Salamanca, Spain.
6
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28006 Madrid, Spain.
7
Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Kanagawa 230-0045, and Laboratory of Lymphocyte Differentiation, World Premier Institute (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.

Abstract

Upon 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.

PMID:
29844052
DOI:
10.1126/scisignal.aal1506

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