Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development (Immunity, 2012, 36:769-781)

報告日期: 2012/10/09
報告時間: 15:10/16:00
報告學生: 羅瑞燕
講評老師: 謝奇璋
附件下載: 下載[1215-1348564494-1.pdf] 

Disruption of Fnip1 Reveals a Metabolic Checkpoint Controlling B Lymphocyte Development

Heon Park et al., Immunity 36: 769–781 (2012)

                           Student: Jui-Yen Lo (羅瑞燕                               Time: 15:10~16:00, Oct. 9, 2012

                            Commentator: Dr. Chi-Chang Shieh (謝奇璋 老師Place: Room 602

Abstract

Based on both the rearrangement status of Ig loci and pre-B cell receptor (pre-BCR) expression, B lymphocyte development in the bone marrow can be divided into four stages, including pre-pro B, pro-B, pre-B and immature B cells.  Pre-B cell stage is a developmental checkpoint to monitor IgH-chain rearrangement and trigger clonal expansion and progression of Igm+ pre-B cells.  Folliculin-interacting protein 1 (FNIP1) has been identified in 20061.  Although the function of FNIP1 is not clear, this protein has been found to interact with and be phosphorylated by AMPK, an enzyme involved in cellular energy homeostasis.  In this study, the authors used an ethylnitrosourea  mutagenesis strategy to generate Fnip1-null mice.  First, they found a B-cell developmental block at the transition from large pre-B to small pre-B cells in  Fnip1-/- mice.  To identify the cause that inhibits B cell development, gene expression levels were compared between Fnip1-/- and wild-type cells using cDNA microarray technology.  The authors found that the majority of the affected genes were involved in cell metabolism and mitochondrial biogenesis.  In particular, there was a significant increase in the expression of regulators in fatty acid oxidation, Pgc1α and Pgc1β.  Fnip1-/- cells showed increased numbers of mitochondria and upregulation of phospho-S6 ribosomal protein (S6R), a downstream target of mTORC1, suggesting an increase in mTOR-mediated metabolism.  In addition, pre-BCR signaling was activated normally in the absence of Fnip1.  However, activation of AMPK failed to inhibit the phosphorylation of mTOR and S6R in Fnip1-/- pre-B cells.  Fnip1 loss resulted in a nutrient and energy deficit, dysregulation of metabolic homeostasis and B-cell developmental arrest in response to nutrient stress.  Finally, the authors found that loss of Fnip1 inhibits pre-B cell lymphomagenesis.  In conclusion, Fnip1 plays a crucial role in metabolic checkpoint during B lymphocyte development.

 

Reference

1. Baba, M. et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and

    is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 103, 15552-15557 (2006).