The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

Abstract

Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases. Bcl-2 nineteen-kilodalton interacting protein (BNIP3) belongs to the Bcl-2 homology domain (BH3)-only Bcl-2 family members because it only contains a putative BH3 domain. 1 The other major domains found in BNIP3 are the PEST domain that targets BNIP3 for degradation, a conserved domain that is conserved from Caenorhabditis elegans to humans and a transmembrane (TM) domain, which targets BNIP3 to the mitochondria (Figure 1). 2 BH3-only containing proteins act as rheostats regulating apoptosis through their BH3 domain by binding to antiapoptotic Bcl-2 family members. However, BNIP3 differs from these members, as its BH3 domain fails to interact with antiapoptotic Bcl-2 family members. 3 Furthermore, deletions of the BH3 domain fail to affect the ability of BNIP3 to induce cell death. 4 Unlike other BH3-only family members, BNIP3 interacts with Bcl-2 and Bcl-X L through its TM domain and N terminus (amino acids 1-49). 3 Deletion of the TM domain blocks the ability of BNIP3 to induce cell death. 4 BNIP3 migrates at 30 and 60 kDa, indicating that BNIP3 is a protein that forms homodimers. This homodimerization is primarily through the TM domain of BNIP3. The unique structure of the TM domain suggests that BNIP3 dimers could act as proton channels in the outer mitochondrial membrane increasing ion conductance. 5 Serine 172 and histidine (His) 173 are residues that are present in the dimerization interface of BNIP3. These residues interact by hydrogen bonds and are essential for dimer formation. 6 Furthermore, mutation of the His 173 to alanine completely abrogated the ability of BNIP3 to induce cell death. 7 Bcl-2 and Bcl-X L can compete for binding to the TM domain, which blocks BNIP3 homodimerization and abrogates the ability of BNIP3 to induce cell death (Fi...

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

“…BNIP3 regulation by a PPARγ agonist in adipocytes So far, the regulation of BNIP3 expression has been focused on hypoxia inducible factor 1, α subunit (basic helix-loop-helix transcription factor) (HIF-1α), a well-known transcription factor activated by hypoxia [16]. It is known that HIF-1α upregulates BNIP3 and that the upregulated BNIP3 consequently activates autophagy, probably for survival against hypoxic stress [48].…”

“…Under certain stress conditions, such as hypoxia, BNIP3 controls mitochondrial quality by removing damaged mitochondria via autophagy/mitophagy, and protects cells from death [15]. This bidirectional action of BNIP3 between apoptosis and autophagy suggests that BNIP3 may be a key regulator of cell fate between cell death and survival during dynamic remodelling [16,17].…”

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

“…39,40 Their existence brings new perspectives to the development of small molecules mimicking the activity of BH3-only proteins. Compounds such as Gossypol, ABT-263 or GX15-070 have been designed to overcome the overexpression of anti-apoptotic proteins in cancer cells.…”

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

“…These experiments revealed down-regulation of BNIP3 mRNA upon ectopic expression of SIM2s, which was independently validated by semiquantitative RT-PCR in DU145/SIM2s.myc stable expressing cells that were not used for the microarray study ( Figure 1a). BNIP3 has long been regarded as a pro-apoptotic Bcl-2 family member (reviewed in Lee and Paik (2006) and Burton and Gibson (2009)). Silencing of BNIP3 correlates to increased pancreatic and colon tumour cell survival in vitro, and tumour progression, chemoresistance and worsened prognosis in vivo (de Angelis et al, 2004;Okami et al, 2004;Akada et al, 2005;Erkan et al, 2005;Bacon et al, 2007;Ishiguro et al, 2007;Mahon et al, 2007).…”