B-cell receptor associated protein 31 (BAP31), a polytopic integral endoplasmic reticulum (ER) membrane protein that is part of a complex that contains Bcl-2/Bcl-X L and procaspase 8, has been implicated in the ER sorting of diverse client membrane proteins. BAP31 has been reported to transport transmembrane proteins, such as MHC-1, CD11b/CD18, and cytochrome 450, from the ER to other cellular components. Our previous study reported that BAP31 associates with the N-terminus of CFTRΔF508 and promotes its retro-translocation from the ER and its degradation by the cytoplasmic 26S proteasome system. Our recent studies demonstrated that BAP31 is involved in T-cell activation, hepatic lipid accumulation, insulin resistance, and could combine with p27 kip1 and regulate its proteasome degradation. Furthermore, BAP31 depletion hindered human embryonic stem cell (hESC) proliferation by arresting cells in the G0/G1 phase and inducing caspase-independent cell death. Recent studies have shown that BAP31 communicates with the ER and mitochondria through contact sites to regulate mitochondrial functions and autophagy and is also considered a novel tumor suppression factor involved in metabolic stress, inducing cell death via the ER stress response.
The cytosolic domain of BAP31 contains two identical caspase recognition sites (AAVD.G). After activation of cell surface death receptors, BAP31 is cleaved by caspase-8 and generates a membrane-embedded fragment called p20BAP31, which has been shown to direct proapoptotic signals between the ER and mitochondria when expressed ectopically. Previous studies have shown that p20BAP31 stimulates ER Ca 2+ release, resulting in the activation of Drp1-dependent fission of mitochondria and enhancing the release of cytochrome c (cyt.c). It is worth mentioning that p20BAP31 was shown to induce apoptosis even in the absence of endogenous BAP31, which can exert dominant-negative (DN) interference with the protein transport functions of full-length BAP31. Furthermore, a previous study identified that ER localized Bcl-2 protects against a Bax/Bak-independent paraptosis-like cell death pathway initiated by p20BAP31. In conclusion, p20BAP31 not only stimulates ER Ca 2+ release, mitochondrial fission, and release of cyt.c to induce cell apoptosis, but also initiates a paraptosis-like cell death pathway. However, the mechanism of p20BAP31-induced cell apoptosis is not fully understood, and whether p20BAP31 can trigger other types of cell death remains unclear.
Programmed cell death (PCD) plays a crucial role in many biological processes. Among the different forms of programmed cell death, cell apoptosis is the most common and best studied and is divided into the extrinsic and intrinsic apoptotic pathways. Both pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In the caspase-dependent pathway, proapoptotic proteins of the Bcl-2 family cause changes in mitochondrial membrane permeability. Previous studies have shown that p20BAP31 stimulates mitochondrial fission; however, the change in mitochondrial membrane potential has not been documented. In the caspase-independent pathway, apoptosis-inducing factor (AIF) was discovered as the first protein that regulates caspase-independent apoptosis, which is released from mitochondria and then translocates to the nucleus, where it contributes to chromatin condensation and DNA degradation. In previous studies, p20BAP31 has been shown to induce the release of cyt.c from mitochondria, but whether AIF can be released from mitochondria is still unknown.
Reactive oxygen species (ROS) are produced through a variety of intracellular and extracellular activities. Excessive cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to the activation of cell death processes such as apoptosis. ROS generation is regulated primarily by NADPH oxidase (NOX) enzymes, which predominantly release hydrogen peroxide (H 2 O 2) and superoxide (O−2); four NADPH oxidases (NOX1, NOX2, NOX4, and NOX5) play a prominent role in homeo
