A1/Bfl-1 in leukocyte development and cell death

Abstract

The function of the anti-apoptotic Bcl-2 family member Bcl2a1/Bfl-1/A1 is poorly understood due to the lack of appropriate loss-of-function mouse models and redundant effects with other Bcl-2 pro-survival proteins upon overexpression. Expression analysis of A1 suggests predominant roles in leukocyte development, their survival upon viral or bacterial infection, as well as during allergic reactions. In addition, A1 has been implicated in autoimmunity and the pathology and therapy resistance of hematological as well as solid tumors that may aberrantly express this protein. In this review, we aim to summarize current knowledge on A1 biology, focusing on its role in the immune system and compare it to that of other pro-survival Bcl-2 proteins.

Fig. 1

PhyloTree: unrooted phylogenetic tree http://www.cbrg.ethz.ch/services/AllAll Mouse proteins: A1-a NP_033872, A1-b NP_031560, A1-d NP_031562, Bcl-2 AAH95964, Bcl-x_LAAA51039, Bcl-w NP_031563, Mcl1 NP_032588.1 and Boo/Diva AAH52690.

Fig. 2

ClustalW2 alignment of mouse Bcl-2 prosurvival homologues http://www.ebi.ac.uk Mouse proteins: A1-a NP_033872, A1-b NP_031560, A1-d NP_031562, Bcl-2 AAH95964, Bcl-x_LAAA51039, Bcl-w NP_031563, Mcl1 NP_032588.1 and Boo/Diva AAH52690. Highlighted in bold the glutamate 78 of A1 and the corresponding residue of the other anti-apoptotic proteins.

Fig. 3

Ribbon structure of (A) Bfl-1 structure pdb file 2vm6 using Swiss-PdbViewer 4.0.4 act on ribbon showing the secondary structure. BH1 domain in green, BH2 in blue, BH3 in yellow BH4 in purple and highlighted the glutamate 78 in the binding groove in gray. (B) Bcl-2 structure pdb file 2xa0 using Swiss-PdbViewer 4.0.4 act on ribbon showing the secondary structure. BH1-domain in green, BH2-domain in blue, BH3-domain in yellow and BH4-domain in purple. (C) Alignments using magic fit in Swiss-PdbViewer 4.0.4 on backbone atoms only. Bfl-1 pdb file 2vm6 red Bcl-2 pdb file 2xa0 blue BH3 only peptide Bim in yellow pdb file 2vm6.

Fig. 4

A1 in leukocyte development. Schematic overview of hematopoiesis with key-check points indicated in which developing leukocytes rely on A1 expression for progression and/or survival. Abbreviations used: hematopoietic stem cell (HSC), common myeloid progenitor (CMP), common lymphoid progenitor (CLP), B cell (B), germinal center (GC), double negative thymocyte (DN), double positive (DP), single positive (SP), T cell (T).