bnip3 as an atypical representative of the bcl-2 protein family. part 1: bnip3, a regulator of non-apoptotic programmed cell death

BNIP3 is classified as a member of the Bcl-2 protein family that regulates programmed cell death and of the BH3-only protein subfamily as it only contains one BH domain. However, the transmembrane domain of BNIP3 is involved in at least some of its pro-apoptotic functions. Although there are some similarities between BNIP3 and other BH3-only proteins, for example the ability to interact with anti-apoptotic Bcl-2 proteins and to induce cytochrome c release from mitochondria, BNIP3 is undoubtedly distinct in regard to its activity and regulatory mechanisms. Not only can BNIP3 activate apoptosis, but also, or perhaps first of all, it can activate necrosis-like cell death due to its direct interaction with the mitochondrial membrane. BNIP3 is also involved is autophagy, but its role in this process is not yet clearly understood. It is possible that the induction or stimulation of autophagy by this protein can simultaneously inhibit apoptosis, for example in cardiac myocytes. In some cells, BNIP3 is sequestered in the nucleus, where it also acts as an anti-apoptotic factor, namely as a repressor of AIF transcription. This activity may enable tumor cells to achieve resistance to chemotherapeutics. Understanding BNIP3 functions and regulatory mechanisms can point to new molecular targets in the treatment of cancer and ischemic heart or brain diseases.