Review
Bcl-XL: A multifunctional anti-apoptotic protein

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Abstract

B-cell lymphoma-extra large (Bcl-XL) is one of the anti-apoptotic proteins of the Bcl-2 family that is localized in the mitochondria. Bcl-XL is one of the key regulators of apoptosis that can also regulate other important cellular functions. Bcl-XL is overexpressed in many cancers, and its inhibitors have shown good therapeutic effects. Bcl-XL interacts with Beclin 1, a key factor regulating autophagy.

Bcl-XL is essential for the survival of neurons and plays protective roles in neuronal injuries. It can promote the growth of neurons and the correct formation of neural networks, enhance synaptic plasticity, and control neurotoxicity. Bcl-XL can also promote the transport of Ca2+ to mitochondria, increase the production of ATP, and improve metabolic efficiency. In addition, targeting Bcl-XL has shown potential value in autoimmune diseases and aging.

In this review, we summarize the functions of Bcl-XL in cancer, autophagy, Ca2+ signaling, neuroprotection, neuronal growth and synaptic plasticity, energy metabolism, immunity, and senescence as revealed by investigations conducted in the past 10 years. Moreover, we list some inhibitors that have been developed based on the functions of Bcl-XL.

Introduction

Apoptosis was first described by Kerr et al. in 1972. The term “apoptosis” was derived from ancient Greek, which meant that petals or leaves fall off or drop off from flowers or trees, and Kerr borrowed it to vividly describe cell death [1]. Apoptosis is an active death process, which occurs under the regulation of specific genes [2]. It plays an important role in eliminating unwanted, redundant, or cancerous cells, and maintaining homeostasis in the body. However, dysregulation of apoptosis can lead to many pathological conditions and diseases such as heart disease, cancer, lymphocyte proliferation and autoimmunity, neurodegenerative diseases, and autoimmune diabetes [3].

Apoptosis is a complex and precisely regulated process, with the Bcl-2 family proteins as key regulators. The bcl-2 gene was first discovered because it was involved in the t(14;18)(q32;q21) chromosomal translocation, which is commonly found in B-cell lymphoma [[4], [5], [6], [7]]. The Bcl-2 family currently includes more than 20 members, which can be divided into two classes, anti-apoptotic proteins and pro-apoptotic proteins (Table 1). The ratio of these two classes of proteins determines the fate of a cell. Anti-apoptotic proteins mainly include Bcl-2, Bcl-XL, Mcl-1, and Bcl-W, and except for Mcl-1, have four BH (Bcl-2 Homology) domains (BH1∼BH4), and Mcl-1 does not contain BH4 domain. Pro-apoptotic proteins can be further divided into two categories. One is multiple BH domain proteins (Bax, Bak, and Bok), which contain three BH domains (BH1∼BH3); the other is BH3-only proteins (Bim, Bad, Bid, Noxa, PUMA, Bmf, Hrk, and Bik). In addition, all these Bcl-2 family members have a C-terminal transmembrane (TM) region [8].

Bcl-X was found to share 44 % homology in amino acid sequence with mouse or human Bcl-2. Two different types of human Bcl-X cDNAs (Bcl-XL and Bcl-XS) were then identified by screening many cDNA libraries. Bcl-XL, a protein consisting of 233 amino acids, has a similar structural domain to Bcl-2. The other Bcl-X protein, Bcl-XS, has 170-amino acids, among which the region with the highest homology to bcl-2 has been deleted [9]. Regarding the ability of these two proteins to regulate apoptotic cell death, Bcl-XL inhibits apoptosis, while Bcl-XS promotes apoptosis [9,10]. In 1996, the three-dimensional structure of human Bcl-XL was determined by X-ray crystallography and nuclear magnetic resonance (NMR) and served as the first definite structure belonging to the Bcl-2 family [11]. The crystal structure of rat and mouse Bcl-XL proteins were resolved in 1997 and 2003, respectively [12,13], which promoted structural studies of other anti-apoptotic proteins in the Bcl-2 family and provided clues for understanding how interactions of Bcl-2 family proteins regulated apoptosis. It also triggered the development of drugs targeting this protein.

The Bcl-XL structure contains eight helices (α1-α8), and its BH domain plays an important role in its tertiary structure. The BH1–BH3 domain forms a hydrophobic pocket where the BH3 domain of the pro-apoptotic protein is inserted to trigger oligomerization. In addition, the BH4 domain of Bcl-XL is involved in its anti-apoptotic activity [14,15]. Interestingly, Bcl-XL can adjust the skeletal conformation of the binding pocket to meet the shape required for binding with different ligands [16], and its BH4 domain has also been reported to be a key regulator of other important cellular functions besides inhibiting apoptosis such as tumor progression and cell migration [17]. Bcl-XL also contains a C-terminal transmembrane (TM) domain composed of a hydrophobic alpha-helix. Furthermore, Bcl-XL interacts with Beclin 1, ultimately inhibiting autophagy. However, proteases from autophagosomes can degrade Bid, thereby affecting Bcl-XL-mediated apoptosis. In addition to acting as a key regulator of apoptosis, Bcl-XL is also involved in the regulation of other important cellular functions. Extensive evidence suggests that Bcl-XL is a potential target for cancer therapy. Bcl-XL can also regulate neural growth and synaptic plasticity, and control neurotoxicity. Bcl-XL may also play a neuroprotective role in some neurological injuries such as traumatic brain injury. In addition, Bcl-XL can regulate the conduction of Ca2+ signaling, ATP synthesis, and increase the efficiency of metabolism. Moreover, Bcl-XL plays an important role in autoimmune diseases and aging.

Based on the function of Bcl-XL, a series of drugs have been designed and developed, and here we list some inhibitors for the treatment of certain diseases. We hope that the detailed description of the functions of Bcl-XL will not only allow readers to attain a more comprehensive understanding of Bcl-XL, but also apply these basic research results to disease therapeutics.

Section snippets

Bcl-XL as a target for cancer treatment

There are two pathways of apoptosis, i.e., extrinsic and intrinsic pathways (Fig. 1). The extrinsic pathways, also known as death receptor pathways, include their ligands such as Fas, tumor necrosis factor receptor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL) receptors, which bind to death receptors and promote the recruitment and conformation of death receptors. Subsequently, caspase-8 is activated to form a complex that in turn cleaves caspase-3/6/7 and initiates apoptosis [18]. The

Bcl-XL and autophagy

In addition to inducing apoptosis, Bcl-2 family proteins have also been associated with autophagy, which is a process in which aging or damaged substances in cells undergo self-degradation using lysosomes and thus is responsible for the degradation and reuse of some long-lived proteins and organelles [71]. Autophagy can be divided into three types: macroautophagy, microautophagy, and molecular chaperone-mediated autophagy [72]. Cells under normal conditions rarely undergo autophagy unless in

Bcl-XL regulates adult neuronal growth and synaptic plasticity

Except for inhibiting mitochondria-mediated apoptosis, the anti-apoptotic protein Bcl-XL also has other effects on healthy adult neurons. Studies have reported that Bcl-XL regulates neuronal growth and synaptic plasticity [[87], [88], [89]] and plays an important role in neuronal network formation [90]. Although Bcl-XL is an anti-apoptotic protein, its absence does not cause instant cell death. However, the absence of Bcl-XL results in the abnormal morphology of neurites that involve a

Bcl-XL shows neuroprotective effects

Bcl-XL, as an anti-apoptotic protein, also possesses neuroprotective functions. Bcl-XL plays a key role in the survival of the developing nervous system [95]. Because the regenerative capacity of central nervous system is limited, neurological injuries are generally irreversible. Stem cell therapy has potential superiority in the treatment of nervous system diseases [96]. For example, traumatic brain injury (TBI) often leads to severe nerve damage, and the transplantation of neural stem cells

Bcl-XL regulates Ca2+ signaling

Mitochondria and endoplasmic reticulum (ER) are important organelles in eukaryotic cells and play important roles in various biological pathways. Mitochondria are involved in energy production, cell apoptosis and cell signaling [109,110]. ER is related to protein folding, lipid metabolism, and so on [111]. Bcl-XL is mainly located in the inner and outer membrane of mitochondria [112] and partially located in endoplasmic reticulum and cytoplasm [113]. The endoplasmic reticulum is the main place

Bcl-XL and metabolism

Besides regulating the signaling of Ca2+ mentioned above, Bcl-XL expression also enhances Ca2+-dependent bioenergetics. Bcl-XL overexpression can increase the consumption of metabolites and reduce the accumulation of lactic acid, indicating that Bcl-XL overexpression can promote the activity of the tricarboxylic acid (TCA) cycle [114]. Bcl-XL interacts with IP3R3 in MAMs to increase Ca2+ transport into mitochondria, thereby enhancing the TCA cycle [118]. Also, the overexpression of Bcl-XL in

Bcl-XL and immunity

Apoptosis is closely associated with immune system development, steady state, and function [124]. In the hematopoietic system, too little apoptosis will lead to autoimmune diseases or blood malignancies, while too much apoptosis will result in lymphocytosis and immune deficiency [124]. Anti-apoptotic protein Bcl-XL is an important regulatory factor in the apoptosis pathway, so what is the relationship between Bcl-XL and immunity? Previous studies have reported that Bcl-XL is highly expressed in

Bcl-XL and aging

Aging is a kind of physiological degeneration that leads to an increase in mortality and decrease in fertility [132]. Bcl-XL is essential to the survival of human umbilical vein endothelial cells (HUVECs) in the elderly [133]. Bcl-XL has also been proven to be associated with the control of cell death in elderly fibroblasts, and the downregulation of Bcl-XL was enough to make the apoptosis level of elderly fibroblasts equal to that of young cells [134]. A recent study in mice showed that

Discussion

Apoptosis plays an important role in the development and clearance of damaged cells, and dysapoptotic disorder can lead to many diseases such as cancer and neurodegenerative diseases. Bcl-XL, one of the key regulators of apoptosis pathway, is overexpressed in many cancers and is linked to disease progression, low survival rates and drug resistance. Therefore, targeting Bcl-XL is an effective strategy for cancer treatment. Drugs targeting Bcl-XL alone or in combination have shown good

Declaration of Competing Interest

None.

Acknowledgments

This work was financially supported by National Natural Science Foundation of China (NSFC) [NOs. 81773594, U1703111, 81473254 and 81773637, 31270399], Program for Liaoning Innovation Talents in University (NO. LR2016002), Liaoning Province Natural Science Foundation (NO. 2019-MS-299), Liaoning Revitalization Talents Program (NO. XLYC1807182), and Shenyang Planning Project of Science and Technology (NO. 18-013-0-46). We thank LetPub (www.letpub.com) for its linguistic assistance during the

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