Bid, a BH3-only multi-functional molecule, is at the cross road of life and death

Bid, BH3-interacting domain death agonist, was initially cloned based in its ability to interact with both Bcl-2 and Bax. Bid contains only the BH3 domain, which is required for its interaction with the Bcl-2 family proteins and for its pro-death activity. Bid is susceptible to proteolytic cleavage by caspases, calpains, Granzyme B and cathepsins. Bid is important to cell death mediated by these proteases and thus is the sentinel to protease-mediated death signals. Protease-cleaved Bid is able to induce multiple mitochondrial dysfunctions, including the release of the inter-membrane space proteins, cristae reorganization, depolarization, permeability transition and generation of reactive oxygen species. Thus Bid is the molecular linker bridging various peripheral death pathways to the central mitochondria pathway. Recent studies further indicate that Bid may be more than just a killer molecule. Deletion of Bid inhibits carcinogenesis in the liver, although this genetic alteration promotes tumorigenesis in the myeloid cells. This is likely related to the function of Bid to promote cell cycle progression into S phase. Bid could be also involved in the maintenance of genomic stability by engaging at mitosis checkpoint. These novel findings indicate that this BH3-only Bcl-2 family protein has a diverse array of functions that are important to both the life and death of the cell.