Apoptotic receptors are a group of cell surface markers discovered in recent years and belong to the tumor necrosis factor receptor superfamily. After they bind to the corresponding ligands, they can transmit apoptotic signals to the cells through a series of signal transduction processes.
Apoptosis is an active, signal-dependent process that can be induced by many factors, such as radiation exposure, toxins, drugs, ischemia and hypoxia, viral infections, and so on. Studies have found that most of these factors trigger the mechanism of apoptosis by activating death receptors. The death receptor is a group of cell surface markers discovered in recent years. It belongs to the tumor necrosis factor receptor superfamily. After binding to the corresponding ligands, it can transmit the apoptotic signal to the interior of the cell through a series of signal transduction processes. This process involves at least 8 families of proteins, including TNF, Fas, Caspase and DR3, which ultimately cause activation of the caspase protease family of apoptosis performers, which cleave the corresponding substrates and cause apoptosis.
TNF-α is a cytokine produced primarily by activated macrophages and is a major exogenous mediator of apoptosis. Most cells in the human body have two TNF-α receptors: TNFR1 and TNFR2. Binding of TNF-α to TNFRl has been shown to initiate pathways leading to caspase activation via the intermediate membrane protein TNF receptor associated death domain (TRADD) and Fas-associated death domain protein (FADD). cIAP1/2 inhibits TNF-α signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8. Binding of this receptor can also indirectly lead to activation of transcription factors involved in cell survival and inflammatory responses. However, signals emanating from TNFR1 may also induce apoptosis in a manner independent of caspase. The link between TNF-α and apoptosis suggests why abnormal production of TNF-α plays a fundamental role in several human diseases, especially autoimmune diseases. The TNF-α receptor superfamily also includes death receptors (DRs) such as DR4 and DR5. These receptors bind to the protein TRAIL and mediate apoptosis. Apoptosis is known to be one of the main mechanisms of targeted cancer therapy. Recently designed luminescent ruthenium complex peptide hybrid (IPH), which mimics TRAIL and binds to death receptors on cancer cells, thereby inducing apoptosis.
Figure 1. Overview of TNF signalling in apoptosis.
The Fas receptor (the first apoptotic signal) (also known as Apo-1 or CD95) is a transmembrane protein of the TNF family that binds to Fas ligand (FasL). The interaction between Fas and FasL results in the formation of a death-inducing signaling complex (DISC) containing FADD, caspase-8 and caspase-10. In certain types of cells (type I), treated caspase-8 directly activates other members of the caspase family and triggers the execution of apoptosis. In other cell types (type II), Fas-DISC initiates a feedback loop that helically increases the release of proapoptotic factors and activation of caspase-8 in mitochondria.
Figure 2. Overview of FAS signalling in apoptosis.
Death Receptor 3 (DR3)
Death Receptor 3 (DR3), also known as the tumor necrosis factor receptor superfamily member 25 (TNFRSF25), is a cell surface receptor of the tumor necrosis factor receptor superfamily that mediates apoptosis signaling and differentiation. The only known TNFSF ligand is TNF-like protein 1A (TL1A).
Caspase plays a central role in the transduction of ER apoptosis signals. Caspase is a highly conserved, cysteine-dependent aspartate-specific protease protein. There are two types of caspase: the initial caspase, caspase 2, 8, 9, 10, 11, 12 and effector caspase, caspase 3, 6, 7. Activation of the promoter cysteine protease requires binding to a specific oligomeric activator protein. These effector promoters, caspase, then activate the effector caspase by proteolytic cleavage. The active effect caspase then degrades many intracellular proteins by proteolysis to perform a cell death program.
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