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Mitochondrial Dysfunction, Immune Systems, Their Diseases, and Possible Treatments
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Elise Jacquin, Eric Hervouet, Michaël Boyer-Guittaut
Autophagy is a cellular catabolic process, described for the first time in the 1960s by Christian de Duve.68 This field attracted some important interest since the 1990s with the characterization of this mechanism in yeast and the discovery of the homolog proteins in humans leading to the attribution of the Nobel Prize to Yoshinori Ohsumi in 2016 for its contribution to the development of the autophagy field.69 Autophagy is an intracellular degradation process leading to the formation of an intracellular double-membrane vesicle, called autophagosome, which engulfs part of the cytoplasm (soluble proteins, protein aggregates or even organelles) and then fuses with the lysosome to induce the degradation of this vesicle and its content. This process is highly regulated by more than 40 ATG (AuTophaGy-related) proteins and can be induced by numerous stress conditions such as starvation, hypoxia, oxidative stress, chemical drugs ? For years, this process has been described as non-selective and the complement of the proteasome since it can degrade aggregates or organelles while proteasome only proteolize soluble proteins. But, during the last decade, a selective function of autophagy has emerged. Indeed, several teams have described specific adapters (P62/SQSTM1, NBR1, OPTN, NDP52, NIX, BNIP3/3L) which interact with specific cargo (the aggregate or organelle to degrade) and a member of the ATG8 family (LC3 or GABARAP family) to induce the specific recruitment of the cargo into the autophagosome leading to its degradation. This selective process has been named according to the cargo degraded: aggrephagy, xenophagy, ribophagy, pexophagy, nucleophagy, glycophagy, mitophagy.
The Mechanical Autophagy as a Part of Cellular Immunity; Facts and Features in Treating the Medical Disorders
Published in Immunological Investigations, 2022
Hany Khalil, Amira Abd ElHady, Khaled A. Elawdan, Dalia Mohamed, Doaa D. Mohamed, Ahmed I Abd El Maksoud, Farha A. El-Chennawi, Bhgat El-Fikiy, Ibrahim H. El-Sayed
The macroautophagy is described in mammalian cells as a variety of distinct steps to form the autophagic vesicles. First, the process is induced via accumulation of malfunction proteins that stimulate the autophagy-related proteins ATGs particularly ATG12/ATG5 and ATG16L to form the preliminary phagophore surrounded the misfolded proteins. The extension of the preliminary phagophore requires the conversion of unconjugated ATG8 (LC3I) to conjugated ATG8 (LC3II) through the active autophagy-related enzymes ATG3 and ATG4. The complete autophagosomes with selected cargo migrate and fuse with lysosomal-vesicles to be degraded and induced the autolysosomes (DJ 2003; Xie and Klionsky 2007). Likewise, xenophagy is the morphological type of autophagy which responsible for arresting the intracellular microbes within the autophagosomes and delivering the microbial cargo into lysosomes for degradation. In general, there are three main types of autophagy: microautophagy, macroautophagy, and CMA. Although each is morphologically distinct, all different types of autophagy culminate in delivering cargo to acidic organelles (lysosomes) for degradation and recycling events.
The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review
Published in Expert Review of Anti-infective Therapy, 2019
Thomas R Laws, Adam W. Taylor, Paul Russell, Diane Williamson
As already mentioned, B. pseudomallei is able to resist intracellular killing. The process known as xenophagy, effectively an autophagic process, is subverted by many pathogens, and autophagy itself is believed to be important in the formation of tumors and chronic inflammatory conditions. There is considerable research interest in manipulating autophagy pathways as a tumor therapy, and stimulation of autophagy is potentially a strategy that could be employed for melioidosis [38].
Bacterial stress response: understanding the molecular mechanics to identify possible therapeutic targets
Published in Expert Review of Anti-infective Therapy, 2021
Amit Kumar, Anu Rahal, Jagdip Singh Sohal, Vivek Kumar Gupta
Other than ISR, two highly conserved signaling modules regulate stress as well as homeostasis [20]. These involve metabolic circuits essentially required for cell. These are mTOR pathway and Xenophagy [1,9]. Xenophagy is nothing but autophagy targeting intracellular bacteria. Autophagy is essential for degradation and recycling of undesired cellular material and organelles [9] and is inhibited by the metabolic checkpoint kinase mTOR [33,34]. Xenophagy involves host proteins that specifically target intra cellular bacteria in cells. These proteins include CALCOCO2/NDP52, OPTN/optineurin, SQSTM1/p62, TECPR1, SPT/septin along with ubiquitin. Xenophagy is supposed to initiate amino acid (AA) starvation caused by both extra- and intracellular bacteria. A study conducted on autophagy [34] has proven that the initiation of process with AA starvation leads to disintegration of mTOR from cellular membrane. Dissociation of mTOR downregulates mTOR activity and activates EIF2AK4/GCN2-EIF2S1/eIF2α/ATF3 signaling series [10,33,34]. The involvement of cellular proteins and signaling cascade may vary with bacteria. The entry of bacteria directly in cytosol can directly affect cellular phosphorylation process and lead to dissociation of mTOR from late endosome or lysosomes (LE/Ly) and simultaneously stimulate stress-signaling cascade EIF2AK4/EIF2S1/ATF3 [33]. The bacteria like Salmonella and Brucella, that remain confined in intra cellular compartment or vacuole like structure produce biphasic response after downregulation of mTOR and AA starvation. Salmonella based study revealed initial phase of mTOR down regulation, AA starvation and activation of ATF3 signaling pathway followed by accumulation of mTORC1 on the surface of salmonella containing vacuole suggesting normalizing conditions by replenishing amino acids from extra cellular compartments [1,33]. All the bacterial cell constituents responsible to induce oxidative stress directly or indirectly activate immune system based on type of defense strategy adopted by host system. Further use of immunosuppressive drugs or disease conditions causing deprived immune system can also support the initiation of disease [14].