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    • Mechanistically it was soon realized that in

    2022-11-18

    Mechanistically, it was soon realized that in undead cells, Dronc promotes the activation of Jun-N-terminal kinase (JNK) signaling as the major inducer of AiP [25], [28] (Fig. 2B,C). However, it has been unknown for a long time how active Dronc promotes JNK signaling. Recently, it was reported that active Dronc promotes the generation of extracellular reactive oxygen species (eROS), which activate JNK signaling in the undead eye disc tissue [26]. If this is the only mechanism by which Dronc activates JNK or if any other mechanisms exist remains to be seen. JNK functions in a positive feedback loop in AiP as it transcriptionally activates hid and reaper, thus amplifying the AiP process [26], [29], [30]. Downstream of JNK signaling, undead rora produce and secrete several mitogens − including Wingless (Wg), a WNT-family member, Decapentaplegic (Dpp), a TGF-β family member, and Spitz (Spi), an EGF homolog (Fig. 2C) [25], [28], [31]. These mitogens then signal to the neighboring cells to initiate proliferation. Although studies using undead models have provided a lot of insight rora into the mechanisms of AiP, the fact that cells are kept alive under constant apoptotic stress might alter their signaling properties, thus compromising the relevance for understanding physiological AiP. Consequently, p35-independent models of AiP have been developed, known as the “genuine” or regenerative AiP models. In the genuine models, tissue ablation is induced by a temporal pulse of apoptosis in a spatially-restricted manner. The affected imaginal discs are then allowed to recover and regenerate the lost tissue through AiP (Fig. 1A) [32]. Studies using the genuine AiP models have mostly corroborated the findings obtained in the undead models [32], [33], although as often seen with the use of different models, there is controversy about the involvement of individual components such as Wg and Dpp in AiP [31]. Nevertheless, the studies using genuine models have confirmed the involvement of JNK signaling for inducing AiP [32], [34]. Along with JNK signaling, p38 and JAK/STAT signaling pathways are also required for genuine AiP. Furthermore, as described above for the undead model, ROS are also generated in the genuine models, and are required for activation of p38 and JNK signaling [33].
    ROS and ROS signaling Reactive oxygen species (ROS) are formed upon partial reduction of oxygen, and include superoxide anions (O2−), hydroxyl radical (OH) and hydrogen peroxide (H2O2) [35]. They are highly unstable with a relatively short half-life. O2− is generally considered to be the primary ROS and is abundantly generated by different endogenous and exogenous factors. O2− is rapidly dismutated to H2O2, and in the presence of Fe2+ or Cu2+ ions, H2O2 can further be converted to OH via a process known as Fenton reaction (Fig. 3). Mitochondria are the primary source of intracellular O2−[36], followed by other organelles such as endoplasmic reticulum (ER), peroxisomes, and the phagosomes in specialized phagocytic cells that display localized generation of ROS (Fig. 3) [37]. In mitochondria, the electron transport chain (ETC) complexes transfer electrons from NADH and succinate to synthesize ATP during aerobic respiration. Leaks in the ETC, especially in complex I and III cause a one electron reduction of molecular O2 to form O2− in the mitochondrial matrix [36]. In the ER, H2O2 is produced by post-translational oxidative modifications during protein folding [37], [38], while in the peroxisomes, ROS are generated as byproducts of catalytic functions of enzymes involved in various metabolic pathways like α- and β-oxidation of very long chain fatty acids, amino acid catabolism, and others [39], [40]. Another major source of ROS are the membrane-associated NADPH oxidases NOX and dual oxidase (DUOX) (Fig. 3). They show widespread localization to different cell and organelle membranes, and account for the generation of extracellular ROS (eROS), in particular via DUOX. They catalyze the reduction of O2 to O2− by using NADPH as an electron donor [41]. These enzymes are evolutionarily conserved in eukaryotes. There are total of 7 NOX family members − NOX1-5 and DUOX1-2 in mammals, while in Drosophila there is one homolog for NOX (dNOX) and one for DUOX (dDUOX), and in C. elegans there is no NOX homolog, but 2 DUOX enzymes present [42]. NOX proteins are characterized by the presence of a carboxy-terminal intracellular Flavin domain that contains binding sites for co-enzymes NADPH and FAD (Fig. 3), an amino-terminal hydrophobic domain that forms 6 transmembranal α-helices with four highly conserved heme-binding histidine residues in the transmembrane domain that act as carrier to transport electrons across the membrane, and an additional amino-terminal intracellular Ca2+-binding EF hand domain observed in NOX5. DUOX proteins have a similar structure as NOX5 with the addition of a seventh transmembrane domain and an extracellular peroxidase-homology domain (PHD) (Fig. 3). Thus, DUOX proteins can generate O2− through the catalytic core and potentially further process it through its own peroxidase domain [41].