Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development

Immunity. 2012 May 25;36(5):769-81. doi: 10.1016/j.immuni.2012.02.019. Epub 2012 May 17.

Abstract

The coordination of nutrient and energy availability with cell growth and division is essential for proper immune cell development and function. By using a chemical mutagenesis strategy in mice, we identified a pedigree that has a complete block in B cell development at the pre-B cell stage resulting from a deletion in the Fnip1 gene. Enforced expression of an immunoglobulin transgene failed to rescue B cell development. Whereas essential pre-B cell signaling molecules were activated normally in Fnip1-null pre-B cells, the metabolic regulators AMPK and mTOR were dysregulated, resulting in excessive cell growth and enhanced sensitivity to apoptosis in response to metabolic stress (pre-B cell receptor crosslinking, oncogene activation). These results indicate that Folliculin-interacting protein 1 (Fnip1) is vital for B cell development and metabolic homeostasis and reveal a metabolic checkpoint that may ensure that pre-B cells have sufficient metabolic capacity to support division, while limiting lymphomagenesis caused by deregulated growth.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cell Differentiation / genetics*
  • Cell Division / genetics
  • Estrone / genetics*
  • Estrone / metabolism*
  • Hematopoiesis / genetics
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / metabolism
  • Mice
  • Mice, Transgenic
  • Precursor Cells, B-Lymphoid / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Carrier Proteins
  • FNIP1 protein, mouse
  • Immunoglobulin Heavy Chains
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Estrone
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse

Associated data

  • GEO/GSE37687