Mechanisms and Biology of B-Cell Leukemia/Lymphoma 2/Adenovirus E1B Interacting Protein 3 and Nip-Like Protein X

Abstract

B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B interacting protein 3 (BNIP3) and Nip-like protein X (NIX) are atypical BCL-2 homology domain 3-only proteins involved in cell death, autophagy, and programmed mitochondrial clearance. BNIP3 and NIX cause cell death by targeting mitochondria, directly through BCL-2-associated X protein-or BCL-2-antagonist/killer-dependent mechanisms, or indirectly through an effect on calcium stores in the endoplasmic reticulum. BNIP3 and NIX also induce autophagy through an effect on mitochondrial reactive oxygen species production, or by releasing Beclin 1 from inhibitory interactions with antiapoptotic BCL-2 family proteins. BNIP3 downregulates mitochondrial mass in hypoxic cells, whereas NIX is required for mitochondrial elimination during erythroid development. BNIP3 and NIX have an emerging role in human health. Cell death mediated by BNIP3 and NIX is implicated in heart disease and ischemic injury. Cancer progression is linked to loss of the prodeath function of BNIP3, but also to induction of its prosurvival activity. Finally, BNIP3 and NIX are implicated in mitochondrial quality control, which is important in aging and degenerative disease. Elucidation of the mechanisms by which BNIP3 and NIX regulate cell death, autophagy, and mitochondrial clearance may lead to treatments for these conditions.

Placental autophagy regulation by the BOK-MCL1 rheostat

“…Previous studies have reported on the role of BNIP3, a BH3-only protein, as regulators of both autophagy and apoptosis in response to hypoxic signaling in cardiac disorders and in cancer. 47,48 However, our findings suggest that the oxidative stress-altered BOK-MCL1 rheostat is the key inducer of autophagy in PE as we were unable to detect altered levels of BNIP3 in PE placentas (data not shown), suggesting that this BH3-only protein may have distinct tissue-specific functions.…”

Mitochondrial autophagy: Origins, significance, and role of BNIP3 and NIX

“…BNIP3 and the closely related protein NIX (approximately 50% identical amino acids) are single-pass, transmembrane proteins, located in the OMM (reviewed in [72]) (Fig. 2).…”

Autophagy-related Protein 32 Acts as Autophagic Degron and Directly Initiates Mitophagy

“…One of the critical points in mitophagy is how the autophagy machinery targets to mitochondria to specifically sequester the energy-converting organelles. Recent studies reveal key proteins that localize to the mitochondrial surface and establish the selectivity of mitochondrial degradation in yeast and mammals (5)(6)(7). In principle, it has so far been hypothesized that those key molecules directly or indirectly participate in recruiting core Atg proteins required for generation of isolation membranes and subsequent formation of autophagosomes.…”