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      Apoptosis and apoptotic body: disease message and therapeutic target potentials

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          Abstract

          Apoptosis is widely known as programmed cell death eliciting no inflammatory responses. The intricacy of apoptosis has been a focus of an array of researches, accumulating a wealth of knowledge which led to not only a better understanding of the fundamental process, but also potent therapies of diseases. The classic intrinsic and extrinsic signaling pathways of apoptosis, along with regulatory factors have been well delineated. Drugs and therapeutic measures designed based on current understanding of apoptosis have long been employed. Small-molecule apoptosis inducers have been clinically used for eliminating morbid cells and therefore treating diseases, such as cancer. Biologics with improved apoptotic efficacy and selectivity, such as recombinant proteins and antibodies, are being extensively researched and some have been approved by the FDA. Apoptosis also produces membrane-bound vesicles derived from disassembly of apoptotic cells, now known as apoptotic bodies (ApoBDs). These little sealed sacs containing information as well as substances from dying cells were previously regarded as garbage bags until they were discovered to be capable of delivering useful materials to healthy recipient cells (e.g., autoantigens). In this review, current understandings and knowledge of apoptosis were summarized and discussed with a focus on apoptosis-related therapeutic applications and ApoBDs.

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          Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

          Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
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            Caspases: the executioners of apoptosis.

            Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1 beta-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Capases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.
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              Molecular characterization of mitochondrial apoptosis-inducing factor.

              Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                07 December 2018
                31 January 2019
                18 January 2019
                : 39
                : 1
                : BSR20180992
                Affiliations
                [1 ]State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
                [2 ]Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou 213164, China
                [3 ]Shenzhen Research Institute of Nanjing University, Shenzhen 518057, China
                Author notes
                Correspondence: Zi-Chun Hua ( zchua@ 123456nju.edu.cn )
                [*]

                These authors contributed equally to this work.

                Article
                10.1042/BSR20180992
                6340950
                30530866
                a5f3b1cc-a327-4e93-a7b9-838d62c2dfe4
                © 2019 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 21 June 2018
                : 30 November 2018
                : 07 December 2018
                Page count
                Pages: 17
                Categories
                Review Articles
                Review Article
                22
                39
                45

                Life sciences
                apoptosis,apoptotic bodies,caspase,death receptors,drug design,intercellular communication

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