The characteristics of Bax inhibitor-1 and its related diseases

Abstract

Bax inhibitor-1 (BI-1) is an evolutionarily-conserved endoplasmic reticulum protein. The expression of BI-1 in mammalian cells suppresses apoptosis induced by Bax, a pro-apoptotic member of the Bcl-2 family. BI-1 has been shown to be associated with calcium (Ca(2+)) levels, reactive oxygen species (ROS) production, cytosolic acidification, and autophagy as well as endoplasmic reticulum stress signaling pathways. According to both in vitro and clinical studies, BI-1 promotes the characteristics of cancers. In other diseases, BI-1 has also been shown to regulate insulin resistance, adipocyte differentiation, hepatic dysfunction and depression. However, the roles of BI-1 in these disease conditions are not fully consistent among studies. Until now, the molecular mechanisms of BI-1 have not directly explained with regard to how these conditions can be regulated. Therefore, this review investigates the physiological role of BI-1 through molecular mechanism studies and its application in various diseases.

Fig. (1)

BI-1 reduces intra-ER and mitochondrial Ca²⁺, leading to cell protection. BI-1 binds to IP₃R and sensitizes IP₃R-induced Ca²⁺ release. Reduced intra-ER Ca²⁺ leads to decreased Ca²⁺ efflux into cytosol and less mitochondrial Ca²⁺ accumulation, resulting cell protection effect (left). BI-1 has a unique function of pH-dependent Ca²⁺ channel or Ca²⁺/H⁺ antiporter activity. Because of the Ca²⁺ leak channel activity, intra-ER and mitochondrial Ca²⁺ is decreased, linked to the cell protection effect (right). However, in severe acidic condition, Ca²⁺ is more accumulated in mitochondria because of the stimulated Ca²⁺ leak from ER membrane in the presence of BI-1 (right).

Fig. (2)

BI-1 protects against ER stress-induced apoptosis. The BI-1-induced protection against ER stress correlates with inhibition of Bax activation and its translocation to the mitochondria, suppressing caspase activation (left). BI-1 dissociates NPR and the P450 2E1 (CYP) complex, reducing ER stress-initiated ROS generation. In addition, BI-1 elevates HO-1 expression through Nrf-2 and ARE, leading to reduced ROS production (right).

Fig. (3)

BI-1 regulates ER stress response. BI-1 stimulates lysosome activity. The enhanced lysosomal protein degradation activity reduces protein folding requirement, leading to the reduced ER stress response (left). BI-1 inhibits IRE-1α phosphorylation and its endonuclease activity through the interaction with IRE-1α, leading to ER stress regulation (right).

Fig. (4)

BI-1 is related with autophagy. BI-1 binds to IP₃R on ER and reduces basal intra ER Ca²⁺, transferring less Ca²⁺ into mitochondria. Decreased mitochondrial Ca²⁺ causes decrease in ATP, leading to AMPK activation and autophagy (left). In the presence of ER stress, IRE-1α binds with TRAF-2, activating JNK and autophagy. BI-1 interacts with IRE-1α, inhibiting the interaction between IRE-1α and TRAF-2 leading to the inhibition of autophagy (right).