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  • Inactivation of the proton pump comes with luminal alkaliniz

    2023-11-30

    Inactivation of the proton pump comes with luminal alkalinization of the targeted vesicles such as lysosomes (Fig. 2b). Lysosome pH can also be raised stoichiometrically by addition of a membrane-permeable weak Biotin-azide such as methylamine or chloroquine which accumulates in its protonated, non-membrane-permeable form. In a different approach pH values can be equilibrated between membranes using ionophores such as nigericin and monensin. These compounds transport monovalent cations through the lipid bilayer in exchange for protons, thereby dissipating pH differences.
    V-ATPase as a regulator of antimicrobial defense by autophagy Not only phagosomes but also autophagosomes are central in keeping the propagation of pathogens in check (for some excellent specialized reviews see (Gomes and Dikic, 2014, Huang and Brumell, 2014, Kimmey and Stallings, 2016)). This can happen through autophagy of complete phagosomes or by direct intracellular recognition of bacteria and their targeting to autophagosomes (xenophagy, summarized in (Gomes and Dikic, 2014)). Xenophagy consequently only occurs with pathogens whose phagosome membrane is disrupted during infection. Similar to phagocytosis, autophagy and xenophagy have been conserved throughout most of the eukaryotic world and they are intimately coupled with the endocytic pathway. During autophagy, a double-membrane-structure wraps itself around cytoplasmic material forming an autophagosome. Similar as is the case with phagosomes, autophagosomes “mature” into autolysosomes by subsequent fusion with lysosome membranes. In the autolysosome, degradation is triggered by the abundant hydrolases in the acidified environment. It is possible that pathogens, regardless of whether in phagosomes or in the cytosol, are incorporated. In this way even pathogens which ‘avoid’ destruction by lysosomes can be eradicated because autophagic membranes pull the camouflage off the pathogen phagosome by wrapping the whole phagosome/vacuole into a regular autophagosome. In an alternative scenario microorganisms damage the phagosome membrane which makes the inner portion of the compartment ‘visible’ for the host cell autophagy machinery. As an example, Salmonella enterica serovar Typhimurium can rupture the phagosome membrane and enter the cytosol. The cytosolic β-galactoside-binding lectin Galectin-8 recognizes the heavy intraluminal glycosylation of damaged phagosomes and initiates an autophagic response: Galectin-8 transiently recruits the nuclear dot protein 52kDa (NDP52), an autophagy receptor, steering the whole Salmonella-containing compartment to autophago(lyso)somes (Thurston et al., 2012, von Muhlinen et al., 2010). Autophagy as a killing mechanism can also be subverted by microbes (Gomes and Dikic, 2014, Huang and Brumell, 2014, Kimmey and Stallings, 2016). Coxiella burnetti and Porphyromonas gingivalis are examples of pathogens which inhibit the formation of autolysosomes and which are not killed in the endolysosomal pathway (Campoy and Colombo, 2009). Listeria monocytogenes and Shigella flexneri can leave the phagosome and reach the cytosol where they multiply. Both pathogens have developed mechanisms to evade autophagy. Shigella releases IcsB and other effectors through its type III secretion system. Bacteria lacking this effector are trapped by autophagy. IcsB binds to VigG, another Shigella protein, and this interaction inhibits the recruitment of the early autophagy protein Atg5. That is, Shigella masks its own surface molecule protecting itself from the autophagic host defense system (Ogawa et al., 2005). Similarly, Listeria prevents degradation and killing by autophagy by surface expression of the ActA protein which prevents ubiquitination, a post-translational modification by attachment of one or more ubiquitin molecules to the pathogen (Yoshikawa et al., 2009). Interestingly, autophagy also keeps Listeria in spacious non-degradative vacuoles in which the bacteria replicate only slowly (Birmingham et al., 2008).