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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / physiology*
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism
  • Cells, Cultured
  • Energy Metabolism*
  • Female
  • Genes, ras*
  • Germinal Center / cytology
  • Germinal Center / physiology*
  • Glycolysis
  • Lymphocyte Activation
  • Male
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Monomeric GTP-Binding Proteins / physiology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / metabolism


  • CD40 Antigens
  • Membrane Proteins
  • Receptors, Antigen, B-Cell
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Rras2 protein, mouse
  • Hras protein, mouse
  • Monomeric GTP-Binding Proteins
  • Proto-Oncogene Proteins p21(ras)