Apoptosis Signaling Pathway


Apoptosis refers to the autonomous, orderly programmed cell death of cells controlled by genes to maintain homeostasis, and plays an important role in maintaining intracellular homeostasis. There are three main apoptotic pathways: the death receptor pathway, the mitochondrial pathway, and the endoplasmic reticulum pathway. Each apoptotic pathway is associated with each other and mediates apoptosis.

Figure 1 Overview of apoptosis pathways

Mitochondrial pathway

The mitochondrial pathway is also known as the endogenous apoptotic pathway. Mitochondria control the living and death of cells in an aerobic environment and are the main site for ATP production. Recent studies have shown that mitochondria are also the main regulatory site for apoptosis and participate in the regulation of most apoptosis. The endogenous apoptotic pathway can be induced by a variety of factors, such as the cell's detachment from the original growth environment, loss of support for growth factors or hormones that depend on it, or DNA damage.

Under the action of various pro-apoptotic signals, MPTP is irreversibly over-opened, mitochondrial transmembrane potential disintegration, respiratory chain uncoupling, mitochondrial matrix osmotic pressure is elevated, endometrial swelling, cytochrome c (Cytc) located in the mitochondrial membrane space and other pro-apoptotic active proteins are released into the cytosol. In the presence of ATP /dATP, Cytc forms a multimeric complex with apoptotic protease activator-1 (Aaaf-1), which activates the caspase-9 precursor, resulting in activation of caspase-3 in downstream effectors, and cleavage of substrates lead to cells apoptosis. Among them, active caspase-3 is a key protease in the cascade reaction and is a common downstream effect part of various apoptotic pathways. Caspase-3 substrates are mostly functional proteins in cells involved in DNA repair, mRNA cleavage, steroid synthesis, and cytoskeletal remodeling.

The Bcl-2 family controls the permeability of the mitochondrial outer membrane and intima and is a major regulator of the mitochondrial apoptotic pathway, which regulates apoptosis by activating a cascade of downstream genes. The Bcl-2 family is divided into three categories: pro-apoptotic proteins (such as Bak and Bax), anti-apoptotic proteins (such as Bcl-2 and Bcl-xL), and BH3-only proteins such as Bim and Bid. BH3-only is a pro-apoptotic protein that regulates apoptosis by inhibiting the activity of Bcl-2 anti-apoptotic members or by activating Bax/Bak-like pro-apoptotic members. In the Bcl-2 family, Bax is a major mediator of the mitochondrial pathway. After Bax is activated, it is transferred from the cytoplasm to the mitochondria, and the mitochondrial membrane permeability is destroyed, which leads to the release of Cytc and the apoptosis of the mitochondrial pathway.

Death receptor pathway

This pathway is an apoptotic pathway induced by extracellular signals and is therefore also referred to as an exogenous apoptotic pathway. There are at least eight death receptors on the surface of mammalian cells: Fas, TNFR1, TNFR2, DR3, DR4, DR5, DcR1, and DcR2, all of which are members of the tumor necrosis factor alpha receptor family. The most typical of these death receptors are Fas and TNFRs.

Fas, also known as APO-1 (ie, CD95 molecule), is a type I membrane protein. Fas is mainly present as a membrane receptor and has a signal transduction effect in apoptosis. FasL is a type II membrane protein on the cell surface. FasL binds to Fas, leading to the formation of a trimeric activation form in the death zone of Fas, followed by recruitment of FADD (Fas-related death domain protein), and FasL-Fas-FADD forms a death-inducing signaling complex (DISC). After DISC formation, it causes cytoplasmic Procaspase-8 molecule activation. The activated Procaspase-8 is linked to each other, further self-activating to initiate a downstream Caspase-associated protease cascade, which ultimately leads to apoptosis. On the other hand, activated Caspase-8 can also cleave Bid in cytoplasm into truncated Bid (tBid). tBid has strong pro-apoptotic activity and acts on mitochondria to release Cytc again, which is promoted apoptosis by Caspase-9/3. In this pathway, the formation of DISC is a critical step in the cascade reaction.

TNF mediates its biological activity through TNFR-I and TNFR-II. TNFR-I contains a highly homologous amino acid sequence (ie, DD) necessary for transduction of cell death signals, and TNFR-II lacks DD, but both receptors mediate apoptosis. TNFRs do not have enzymatic activity but can recruit other molecular transduction signals. Upon binding to TNF, TNFR-I is trimerized and then a TNFR-associated death domain is recruited. TRADD can cause activation of two signal transduction pathways: (1) Inducing apoptosis by recruiting FADD, which activates apoptotic pathway by recruiting and activating Caspases; (2) by tumor necrosis factor receptor-associated protein 2 (TRAF-2) and induction of transcription factor (RIP) activation. TRAF-2 and RIP activate NF-κB-inducible kinase (NIK), which phosphorylates NF-κB inhibitory proteins and promotes the degradation and release of NF-κB. The latter translocates to the nucleus and activates a series of gene expression, leading to apoptosis.

Endoplasmic reticulum pathway

The ERS pathway is also an endogenous apoptotic signaling pathway. As an important organelle in cells, ER participates in activities such as folding of cells after protein synthesis, the reaction of cells to stress, and is also the main reservoir of Ca2++. ERS primarily induces apoptosis through three signaling factors that activate cascades, including PERK, IRE1α, and ATF6. These three factors and BiP/GRP78 constitute a stable mixture to prevent the occurrence of UPR, which is divided into a BiR/GRP78-dependent UPR pathway and a non-dependent BiP/GRP78-activated UPR pathway. Shima et al. demonstrated that the expression of BiP /GRP78 can be enhanced to attenuate ERS, thereby reducing apoptosis. At the same time, experiments have shown that ATF6 and PERK can be activated by vascular endothelial growth factor receptor-phospholipase Cγ-mTOR complex 1 to induce ERS. IRE1α can be activated by activated PI3K/AKT.

ERS causes apoptosis mainly by regulating the Bcl-2 family. Recent studies have also shown that apoptosis can also be controlled by regulating the transformation efficiency of anti-apoptotic proteins, such as massive phosphorylation of eIF2α leading to accumulation of cytoplasmic heterogeneous nuclear ribonucleoprotein A1, thereby reducing anti-apoptosis such as Bcl-xL. The efficiency of expression of the factor ultimately induces apoptosis in the cells. In addition, Hacker found that ERS is also involved in the inflammatory pathway, ERS causes IL-1β expression through the PERK and IRE1 pathways, and IL-1β positively regulates ERS-mediated β cell death.

ROS and Ca2++ are two important factors that influence apoptosis. High concentrations of ROS promote ERS. In addition, when ERS activates JNK, ROS in the mitochondria increase, and finally induce apoptosis, which can be seen as the intersection of two apoptotic pathways. ER, mitochondria and nucleus are the main reservoirs of Ca2+. When ERS occurs, ER will release Ca2++ to increase the intracytoplasmic Ca2++ concentration, and the mitochondrial Ca2++ concentration will also increase. The Ca2++ concentration will increase, which will cause the Ca2++ modulation network overload to cause mitochondrial dysfunction, which will eventually occur apoptosis.

Figure 2 A model for the regulation of lifespan by mtROS signaling through the intrinsic apoptosis pathway

Apoptosis and diseases

Excessive apoptosis can lead to AIDS, neurodegenerative diseases, blood diseases (such as pernicious anemia) and tissue damage. In order to inhibit the occurrence of apoptosis, it is possible to inhibit caspase activity and reduce the number of death ligand receptors. For example, cold-inducible RNA-binding protein (CIRP) may inhibit apoptosis-protected neurons through the mitochondrial pathway. Erythropoietin, a mammalian target of rapamycin (mTOR), prevents glial cells from dying. 9-Hydroxy epinootkatol (9OHEN) protects glutamate-induced neuronal apoptosis by inhibiting glutamate-induced caspase-3 activation. T. cruzi trans-sialidase (TcTS) synergizes with host ciliary neurotrophic factor or leukemia inhibitory factor can affect Bcl-2 and PI3K/Akt, and protect against trypanosomiasis neurons make neurons not apoptotic.


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