In multicellular organisms, cell death is a critical and active process that maintains tissue homeostasis and eliminates potentially harmful cells. There are three major types of morphologically distinct cell death: apoptosis (type I cell death), autophagic cell death (type II), and necrosis (type III). All three can be executed through distinct, and sometimes overlapping, signaling pathways that are engaged in response to specific stimuli. Apoptosis is triggered when cell-surface death receptors such as Fas are bound by their ligands (the extrinsic pathway) or when Bcl2-family proapoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both pathways converge on the activation of the caspase protease family, which is ultimately responsible for the dismantling of the cell. Autophagy defines a catabolic process in which parts of the cytosol and specific organelles are engulfed by a double-membrane structure, known as the autophagosome, and eventually degraded. Autophagy is mostly a survival mechanism; nevertheless, there are a few examples of autophagic cell death in which components of the autophagic signaling pathway actively promote cell death. Necrotic cell death is characterized by the rapid loss of plasma membrane integrity. This form of cell death can result from active signaling pathways, the best characterized of which is dependent on the activity of the protein kinase RIP3.
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The caspase protein family. Initiator caspases (caspase-2, caspase-8, and caspase-9) are the apical caspases of the apoptotic-signaling cascade. Initiator caspases are produced as inactive zymogens composed of a prodomain (containing a CARD or a death effector domain [DED]) and a large and small subunit. They are recruited through their prodomains into large activation platforms and activated by dimerization. In contrast, executioner caspases (caspase-3, caspase-6, and caspase-7) are activated by cleavage of the zymogen between the large and small subunits and are therefore dependent on initiator caspases for their activation. Catalytically active caspases are composed of a heterotetramer of two small and two large subunits.
The mitochondrial apoptotic pathway. In response to various cellular stresses, proapoptotic members of the Bcl2 family induce mitochondrial outer membrane permeabilization (MOMP), allowing the release into the cytosol of proapoptotic factors that are normally sequestered in the intermembrane space of the mitochondria (including cytochrome
c, Smac, and Omi). In the cytosol, cytochrome c binds to APAF1 and triggers its oligomerization. Caspase-9 is then recruited and activated by this platform, known as the apoptosome. Catalytically active caspase-9 cleaves and activates the executioner caspases-3 and -7. Upon release in the cytosol, Smac and Omi bind to and inhibit the caspase inhibitor X-linked inhibitor of apoptosis (XIAP). In doing so, they relieve XIAP inhibition of caspase-9, caspase-3, and caspase-7, and potentiate overall caspase activation by the apoptosome.
Regulation of mitochondrial outer membrane integrity by the Bcl2 protein family. (
A) Members of the Bcl2 protein family are characterized by the presence of one or more Bcl2 homology (BH) region. The antiapoptotic Bcl2 proteins (e.g., Bcl2, Bcl-xL, and Mcl1) and the proapoptotic effectors (e.g., Bax and Bak) share four BH regions and a similar globular structure. BH3-only proteins (e.g., Bid, Bim, Bad, and Noxa) are characterized by a single BH region (BH3). ( B) The proapoptotic effectors reside in cells in inactive forms tethered to the outer mitochondrial membrane (Bak) or soluble in the cytosol (Bax). Upon activation, Bax and Bak oligomerize and further insert into the membrane, causing mitochondrial outer membrane permeabilization (MOMP) and thus apoptosis. ( C) Bax/Bak activation is triggered following the transient binding of a subset of direct activator BH3-only proteins (e.g., Bid and Bim). Antiapoptotic Bcl2 proteins inhibit MOMP by sequestering the direct activator proteins and/or the effectors. Another group of BH3-only proteins, called sensitizers or derepressors (e.g., Bad and Noxa) promote MOMP by antagonizing antiapoptotic Bcl2 proteins, thereby releasing both direct activator BH3-only proteins and Bax/Bak.
Death receptor signaling pathway. The death receptor signaling pathway is triggered by ligation of a death receptor (TNFR1, Fas, or TRAIL-R1/2) and potentially leads to three different outcomes: survival, apoptosis, or necrosis. (
A) Upon ligation (by FasL and TRAIL, respectively), Fas/CD95 and TRAIL-Rs assemble a caspase-activation platform called the DISC. This platform recruits and activates caspase-8 via the adaptor protein FADD and thus engages the extrinsic apoptotic pathway. ( B) Upon ligation to TNF, TNFR1 recruits the adaptor protein TRADD and the kinase RIP1, which in turn mobilizes additional partners, such as the ubiquitin ligases TRAF2 and cIAP1/2. These catalyze the nondegradative ubiquitylation of RIP1 as well as other components of the protein complex, resulting in the stabilization of a prosurvival and proinflammatory signaling platform called complex I. ( C) The removal of ubiquitin chains of RIP1 by inhibition of cIAP1/2 or through the action of deubiquitylases destabilizes complex I, thus allowing the release of TRADD and RIP1. TRADD and RIP1 then promote the formation of a series of cytosolic complexes (complex II) that can initiate either apoptotic or necrotic cell death. In the proapoptotic configuration of the complex, TRADD and RIP1 recruit FADD and caspase-8, resulting in caspase activation and apoptosis. When FADD or caspase-8 are absent, or when caspase activity is blocked, RIP1 binds to and activates RIP3, thus triggering necrotic cell death. Expression of FLICE-like inhibitory protein (FLIP) inhibits the activity of both complexes. FLIP forms a heterodimer with caspase-8 that cannot induce apoptosis but still displays catalytic activity, and this activity antagonizes the activation of RIP3. Therefore, complexes containing FLIP–caspase-8 heterodimers simultaneously block apoptosis and RIP-dependent necrosis.
The inflammasomes. The inflammasomes are caspase-activation platforms that assemble in response to infectious agents (e.g., viruses, bacteria, and fungi) and inert substances that induce inflammation (e.g., uric acid crystals, calcium phosphate crystals, alum, asbestos). They recruit and activate the inflammatory caspase-1 and -11. The caspase-1 activation platforms are supported by the NOD-like receptors (NLRs; e.g., NLRP3 and NLRC4) and AIM. Upon activation by inflammatory agents, these proteins recruit the adaptor molecule ASC and caspase-1. The subsequent activation of caspase-1 induces cleavage and secretion of two inflammatory cytokines, interleukin (IL) 1β and IL18.
The autophagic signaling pathway. Under metabolic stress, AMPK activation and/or mTORC1 inhibition lead to the activation of the preinitiation complex (ULK1, FIP200, and ATG13). The latter activates the initiation complex (beclin 1, VPS15, and VPS34) that generates PI3P and recruits ATG7 to the phagophore. ATG7 functions similarly to an E1-ubiquitin ligase and initiates two conjugation pathways necessary for membrane elongation and closure of the autophagosome. In the ATG5-ATG12 conjugation pathway, ATG12 is sequentially transferred to ATG7, ATG10, and ATG12. The ATG5-12 conjugate recruits ATG16L and forms a complex necessary to stabilize the phagophore and to complete the second conjugation pathway. In the LC3-PE pathway, LC3 is cleaved by ATG4 and sequentially conjugated to ATG7 and ATG3. The ATG5-ATG12-ATG16L complex carries out the final step by transferring LC3 to PE to form an LC3-PE conjugate (also called LC3-II). LC3-II associates with the autophagosomal membrane and is crucial for the targeting of autophagosomes to lysosomes, as well as for the selective autophagy of organelles and protein aggregates.
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Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytoch …
Fas Triggers an Alternative, caspase-8-independent Cell Death Pathway Using the Kinase RIP as Effector Molecule
N Holler et al.
Nat Immunol 1 (6), 489-95.
Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent ne …
Synergistic Induction of Apoptosis and Caspase-Independent Autophagic Cell Death by a Combination of Nitroxide Tempo and Heat Shock in Human Leukemia U937 Cells
QL Zhao et al.
Apoptosis 15 (10), 1270-83.
We have shown that heat stress or a superoxide dismutase mimic nitroxide, Tempo, induces apoptosis, while their combination causes nonapoptotic cell death; however, the u …
The Role of Cell Signalling in the Crosstalk Between Autophagy and Apoptosis
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Not surprisingly, the death of a cell is a complex and well controlled process. For several decades, apoptosis, the first genetically programmed death process to be ident …
Apoptotic and Necrotic Cell Death Induced by Death Domain Receptors
G Denecker et al.
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Apoptosis and necrosis are two distinct forms of cell death. Caspases are indispensable as initiators and effectors of apoptotic cell death and are involved in many of th …
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