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.
Highlights
In mammals, cell death can proceed via the ‘intrinsic’ or the ‘extrinsic’ pathway, both converging upon the activation of caspases that mediate cell demolition.[2,3,6,7,8,9] Activation of the extrinsic pathway is triggered by ligation of ‘death receptors’, members of the tumor necrosis factor receptor (TNFR) family with an intracellular ‘death domain’ on the surface of the cell.[2]
Members of the BCL-2 family can be classified into three subgroups: the pro-survival proteins (BCL-2, MCL-1, BCL-XL, BCL-W, A1) that are critical for cell survival; the BAX/BAK-like multi-BH domain containing pro-apoptotic proteins (BAX, BAK, BOK) that permeabilize the mitochondrial outer membrane (MOMP), and the pro-apoptotic BH3-only proteins (BIM, BID, PUMA, NOXA, BIK, BAD, BMF, HRK) that initiate signaling through the intrinsic apoptotic pathway.[3,10,11]
BOK was first isolated from a yeast two-hybrid screen as a protein that interacted with MCL-1.21 Subsequent in vitro studies demonstrated that enforced BOK overexpression could induce apoptosis, suggesting that it functions in a pro-apoptotic manner, similar to BAX and BAK
Summary
Cell death can proceed via the ‘intrinsic’ ( called ‘BCL-2 regulated’, ‘mitochondrial’ or ‘stress’) or the ‘extrinsic’ ( called ‘death receptor’) pathway, both converging upon the activation of caspases that mediate cell demolition.[2,3,6,7,8,9] Activation of the extrinsic pathway is triggered by ligation of ‘death receptors’, members of the tumor necrosis factor receptor (TNFR) family with an intracellular ‘death domain’ on the surface of the cell.[2]. The few survivors exhibited several phenotypic abnormalities, including webbed feet, substantial neuronal and lymphoid cell accumulation, as well as profound resistance of their lymphocytes (and other cell types) to a broad range of apoptotic stimuli.[17,19,20] Perhaps surprisingly, several tissues in these Bax−/−Bak−/− mutants such as the bladder, liver, heart and pancreas still developed normally and functioned at physiological levels,[17] suggesting that another protein may be involved in the activation of the effector phase of apoptosis in some circumstances One such candidate is BOK, a BCL-2 family member showing 470% amino acid sequence homology to BAX and BAK 21,22. These findings imply that BOK may act in a manner that is fully redundant with the functions of BAX and BAK, or may have a function that is yet unknown
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