title: Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development.
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.
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190, USA.
authors.forename: Heon
authors.initials: H
authors.lastname: Park
authors.forename: Karen
authors.initials: K
authors.lastname: Staehling
authors.forename: Mark
authors.initials: M
authors.lastname: Tsang
authors.forename: Mark W
authors.initials: MW
authors.lastname: Appleby
authors.forename: Mary E
authors.initials: ME
authors.lastname: Brunkow
authors.forename: Daciana
authors.initials: D
authors.lastname: Margineantu
authors.forename: David M
authors.initials: DM
authors.lastname: Hockenbery
authors.forename: Tania
authors.initials: T
authors.lastname: Habib
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.forename: George
authors.initials: G
authors.lastname: Carlson
authors.forename: Brian M
authors.initials: BM
authors.lastname: Iritani
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D004970:Estrone / Q000235:genetics* / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; D007143:Immunoglobulin Heavy Chains; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D004970:Estrone; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases