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Impact of the combined loss of BOK, BAX and BAK on the hematopoietic system is slightly more severe than compound loss of BAX and BAK.

ABSTRACT: It is well established that BAX and BAK play crucial, overlapping roles in the intrinsic pathway of apoptosis. Gene targeted mice lacking both BAX and BAK have previously been generated, but the majority of these animals died perinatally. BOK is a poorly studied relative of BAX and BAK that shares extensive amino acid sequence homology to both proteins, but its function remains largely unclear to date. To determine whether BOK plays an overlapping role with BAX and BAK, we utilized a hematopoietic reconstitution model where lethally irradiated wild type mice were transplanted with Bok(-/-)Bax(-/-)Bak(-/-) triple knockout (TKO) fetal liver cells, and compared alongside mice reconstituted with a Bax(-/-)Bak(-/-) double knockout (DKO) hematopoietic compartment. We report here that mice with a TKO and DKO hematopoietic system died at a similar rate and much earlier than control animals, mostly due to severe autoimmune pathology. Both TKO and DKO reconstituted mice also had altered frequencies of various leukocyte subsets in the thymus, bone marrow and spleen, displayed leukocyte infiltrates and autoimmune pathology in multiple tissues, as well as elevated levels of anti-nuclear autoantibodies. Interestingly, the additional deletion of BOK (on top of BAX and BAK loss) led to a further increase in peripheral blood lymphocytes, as well as enhanced lymphoid infiltration in some organs. These findings suggest that BOK may have some functions that are redundant with BAX and BAK in the hematopoietic system.

SUBMITTER: Ke F

PROVIDER: S-EPMC4632322 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Consequences of the combined loss of BOK and BAK or BOK and BAX.

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Project description:Mitochondrial outer membrane permeabilisation (MOMP) is the point of no return in many forms of apoptotic cell death. The killing effect of MOMP is twofold; it both initiates a proteolytic cascade of pro-apoptotic enzymes and damages mitochondrial function. Accordingly, prevention of MOMP can rescue cells from death. It is clear that either Bak or Bax, which are Bcl-2 family members, are required for MOMP to occur; however, the pore complexes that are formed by Bak and Bax remain poorly defined in terms of their composition, size, number and structure, as well as the mechanism by which they are regulated by other Bcl-2 family members. We recently reported that a key step leading to Bak homo-oligomerisation following an apoptotic stimulus involves transient exposure of the Bak BH3 domain before it binds to the hydrophobic groove of another activated Bak molecule to form a novel symmetric dimer. To form the higher-order oligomers that probably constitute the apoptotic pore complex, Bak dimers then interact via regions away from the BH3 domain and groove. The BH3:groove interaction within Bak homodimers supports a general model to explain the associations between Bcl-2 family members. In this Commentary, we discuss the implications of these findings for the regulation of apoptosis by Bcl-2 family proteins.

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