1. Apoptosis

Apoptosis

Apoptosis Signaling Pathway:

Overview of Apoptosis:

Cell apoptosis, sometimes called programmed cell death, is a cellular self-destruction method to remove old and damaged cells during development and aging to protect cells from external disturbances and maintain homeostasis. Apoptosis also occurs as a defense mechanism such as in immune reactions or when cells are damaged by disease or noxious agents.

Apoptosis is controlled by many genes and involves two fundamental pathways: the extrinsic pathway, which transmits death signals by the death receptor (DR), and the intrinsic or mitochondrial pathway. The extrinsic apoptotic pathway is activated by the binding of the death ligand to DRs, including FasL, TNF-α, and TRAIL, on the plasma membrane. The DR, adaptor protein (FADD), and associated apoptosis signaling molecule (caspase-8) form the death-inducing signaling complex (DISC), thus leading to the activation of the effector caspase cascade (caspase-3, -6, and -7). The mitochondria-mediated intrinsic apoptosis pathway is regulated by Bcl-2 family proteins, including proapoptotic (Bid, Bax, Bak) and antiapoptotic proteins (Bcl-2, Bcl-xL).

Abnormalities in cell apoptosis can be a significant component of diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and neurode-generative diseases. These diseases may benefit from artificially inhibiting or activating apoptosis. A short list of potential methods of anti-apoptotic therapy includes stimulation of the IAP (inhibitors of apoptosis proteins) family of proteins, caspase inhibition, PARP (poly [ADP-ribose] polymerase) inhibition, stimulation of the PKB/Akt (protein kinase B) pathway, and inhibition of Bcl-2 proteins.

Ferroptosis and necroptosis are recently recognized forms of regulated cell death that differs considerably from apoptosis. Misregulated ferroptosis or necroptosis have also been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, etc.

 

References:

[1] Susan Elmore. Toxicol Pathol. 2007; 35(4): 495–516.

[2] Cao L, et al. J Cell Death. 2016 Dec 29;9:19-29.

[3] Dasgupta A, et al. Int J Mol Sci. 2017 Jan; 18(1): 23.

[4] Xie Y, et al. Cell Death Differ. 2016 Mar;23(3):369-79.

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Upon binding to their cognate ligand, death receptors such as Fas and TRAILR can activate initiator Caspases (Pro-caspase 8 and Pro-caspase 10) through dimerization mediated by adaptor proteins such as FADD and TRADD. Active Caspase 8 and Caspase 10 then cleave and activate the effector Caspase 3, 6 and 7, leading to apoptosis. ROS/DNA damage and ER stress trigger Caspase 2 activation. Active Caspase 2 cleaves and activates Caspase 3 and initiates apoptosis directly. Caspase 2, 8 and 10 can also cleave Bid, stimulate mitochondrial outer membrane permeabilization (MOMP) and initiate the intrinsic apoptotic pathway. Following MOMP, mitochondrial intermembrane space proteins such as Smac and Cytochrome C are released into the cytosol. Cytochrome C interacts with Apaf-1, triggering apoptosome assembly, which activates Caspase 9. Active Caspase 9, in turn, activates Caspase 3, 6 and 7, leading to apoptosis. Mitochondrial release of Smac facilitates apoptosis by blocking the inhibitor of apoptosis (IAP) proteins. 

 

Following the binding of TNF to TNFR1, TNFR1 binds to TRADD, which recruits RIPK1, TRAF2/5 and cIAP1/2 to form TNFR1 signaling complex I. Formation of the complex IIa and complex IIb is initiated either by RIPK1 deubiquitylation mediated by CYLD or by RIPK1 non-ubiquitylation due to depletion of cIAPs. The Pro-caspase 8 homodimer in complex IIa and complex IIb generates active Caspase 8. This active Caspase 8 in the cytosol then carries out cleavage reactions to activate downstream executioner caspases and thus induce classical apoptosis[1][2]

 

Reference:

[1]. Thomas C, et al. Caspases in retinal ganglion cell death and axon regeneration. Cell Death Discovery volume 3, Article number: 17032 (2017)
[2]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die.Nat Rev Immunol. 2015 Jun;15(6):362-74.