Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development.
Publication Title
Immunity
Document Type
Article
Publication Date
5-25-2012
Keywords
washington; isb; AMP-Activated Protein Kinase Kinases; Animals; Apoptosis; B-Lymphocytes; Carrier Proteins; Cell Differentiation; Cell Division; Estrone; Hematopoiesis; Immunoglobulin Heavy Chains; Mice; Mice, Transgenic; Precursor Cells, B-Lymphoid; Protein Kinases; Proto-Oncogene Proteins c-myc; Signal Transduction; TOR Serine-Threonine Kinases
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.
Specialty/Research Institute
Institute for Systems Biology
DOI
10.1016/j.immuni.2012.02.019
