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Review
. 2013 May;1285(1):59-79.
doi: 10.1111/nyas.12045. Epub 2013 Mar 25.

Getting Away With Murder: How Does the BCL-2 Family of Proteins Kill With Immunity?

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Free PMC article
Review

Getting Away With Murder: How Does the BCL-2 Family of Proteins Kill With Immunity?

Thibaud T Renault et al. Ann N Y Acad Sci. .
Free PMC article

Abstract

The adult human body produces approximately one million white blood cells every second. However, only a small fraction of the cells will survive because the majority is eliminated through a genetically controlled form of cell death known as apoptosis. This review places into perspective recent studies pertaining to the BCL-2 family of proteins as critical regulators of the development and function of the immune system, with particular attention on B cell and T cell biology. Here we discuss how elegant murine model systems have revealed the major contributions of the BCL-2 family in establishing an effective immune system. Moreover, we highlight some key regulatory pathways that influence the expression, function, and stability of individual BCL-2 family members, and discuss their role in immunity. From lethal mechanisms to more gentle ones, the final portion of the review discusses the nonapoptotic functions of the BCL-2 family and how they pertain to the control of immunity.

Figures

Figure 1
Figure 1
The major signaling pathways leading to cellular apoptosis. The extrinsic pathway of apoptosis (upper left corner) is engaged by plasma membrane associated death receptors belonging to the TNF-R (tumor necrosis factor receptor) superfamily (e.g., TNF-R1/2, CD95/FAS). Upon engagement of these receptors by their respective ligands (e.g., TNF-α, FASL), conformation changes within the trimerized receptor/ligand complexes recruits adaptor proteins (e.g., FADD) and caspase-8 (and/or caspase-10 in human; represented in blue) to assemble a death inducing signaling complex, referred to as the DISC. Assembly of the DISC promotes caspase-8 activation; cleavage and activation of executioner caspases-3, -6 or -7 (represented in green), and cell death.[165] The intrinsic pathway (also called mitochondrial pathway of apoptosis) responds to cellular stresses like DNA damage (through p53), viral infection, protein misfolding, and oxidative-stress. These signals converge to activate the pro-apoptotic proteins of the BCL-2 family. Pro-apoptotic effectors (e.g., BAX, in blue) are able to target mitochondria and induce mitochondrial outer membrane permeabilization (MOMP); in which numerous pro-apoptotic proteins of the intermembrane space (e.g., cytochrome c, the second mitochondrial-derived activator of caspases SMAC/DIABLO, and HtrA2/Omi) are released into the cytosol. Direct activator BH3-only proteins (e.g., BID and BIM, in yellow) and other signals (e.g., p53 or sphingolipids from the ER) facilitate the activation of BAX and BAK. Sensitizers/de-repressors (e.g., BAD and Noxa, in green) interact with the anti-apoptotic members (e.g., BCL-2 and BCL-xL, in red) to lower the cell death threshold. Once in the cytosol, cytochrome c interacts with the adaptor protein apoptotic protease activating factor 1 (APAF-1) to form the apoptosome, which triggers the recruitment and the activation of the caspase-9 (represented in purple). Inhibitors of apoptosis (IAPs) inhibit caspase activation, and SMAC/DIABLO relieves this inhibition. Once initiator caspases (e.g., caspases-8 and -9) are activated, they trigger downstream activation of effector caspases-3 and -7, which cleave numerous cellular substrates including the inhibitor to the caspase activated DNAse (iCAD). Additionally, granzyme B, which is released by cytotoxic T cells, can also directly trigger effector caspase activation to promote cell death. The extrinsic pathway can also engage the intrinsic pathway via caspase-8-mediated cleavage of BID (in yellow) to amplify pro-apoptotic signaling.
Figure 2
Figure 2
The BCL-2 family: primary structure, domains, and hierarchy. The anti-apoptotic members of the BCL-2 family are represented in the red frame. The pro-apototic effectors and the BH3-only are in the blue and green frames, respectively. The BCL-2 homology (BH) domains and the secondary structure (α helices) are represented for each member and the UniProt[166] identifier is indicated between parentheses. Anti-apoptotics and pro-apototic effectors have up to four BH domains. The BH1–3 domains (in purple and blue) are spatially close to each other and form a hydrophobic groove which is important for the interaction with the members of the family. Most of the BH3-only proteins are intrinsically unstructured in solution, and acquire a secondary structure upon interaction with other members of the family.[167,168] An exception is BID, which is phylogenically[169] and structurally[169,170] most similar to the folded members than to the other BH3-only proteins and natively structured.
Figure 3
Figure 3
Interactions and mechanisms of the BH3-only proteins. BH3-only proteins are subdivided in two groups. Sensitizers (in green) selectively interact with anti-apoptotic BCL-2 proteins (in red); as an example, BAD binds to BCL-2, BCL-xL, and BCL-w; whereas Noxa binds to MCL-1 and A1. By binding to the anti-apoptotic BCL-2 proteins, sensitizers prevent the sequestration of the pro-apoptotics and prime for BAX/BAK activation. Direct activators (in yellow) have a broad interaction range within the BCL-2 family. They are able to interact directly with and activate BAX and BAK to induce MOMP. On the other hand they can also counteract the anti-apoptotics. When pro-apoptotics are sequestered by anti-apoptotics, de-repressor BH3-onlys are able to disrupt these complexes. BID and BIM are well characterized direct activators BH3-only proteins[171,172], however the role of PUMA as direct activator remains controversial.[–175] Lines with stops and arrows indicate an inhibition and an activation, respectively.
Figure 4
Figure 4
The BCL-2 family in hematopoiesis. The proteins of the BCL-2 family contribute to numerous steps of both the innate and adaptive immune system development. The adaptive immune system originates from common lymphoid progenitors (CLP) and is comprised of B cells and T cells. The BCL-2 family is a critical regulator of most of the lymphocyte differentiation stages (e.g., the positive and negative selections, in which double positive (DP) cells are maturated in single positive (SP) cells, or the differentiation into memory lymphocytes). The innate immune system originates from common myeloid progenitors (CMP) and, similarly, differentiation of the myeloid cells is controlled by the BCL-2 family. Numbers in brackets refer to the bibliography.

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