Disruption of Fnip1 Reveals a Metabolic Checkpoint Controlling B Lymphocyte Development

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (211 K)Download as PowerPoint slideHighlights► A deletion in the Fnip1 gene blocks B cell development at the pre-B cell stage ► Fnip1 controls metabolic homeostasis and survival during pre-B cell activation ► Fnip1 is required for AMPK to inhibit mTOR-mediated pre-B cell growth ► Fnip1−/− pre-B cells are resistant to lymphoma formation induced by c-Myc