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• W2808078136 abstract "Listeriolysin O (LLO) perforates host vacuoles, allowing Listeria monocytogenes to escape to the cytosol. How cytosolic LLO prevents cell lysis was not understood. In this issue of Cell Host & Microbe, Chen et al., 2018Chen C. Nguyen B.N. Mitchell G. Margolis S.R. Ma D. Portnoy D.A. The listeriolysin O PEST-like sequence co-opts AP-2-mediated endocytosis to prevent plasma membrane damage during Listeria monocyogenes infection.Cell Host Microbe. 2018; 23 (this issue): 786-795Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar show that a PEST sequence prevents cytotoxicity by mediating LLO endocytosis from the plasma membrane. Listeriolysin O (LLO) perforates host vacuoles, allowing Listeria monocytogenes to escape to the cytosol. How cytosolic LLO prevents cell lysis was not understood. In this issue of Cell Host & Microbe, Chen et al., 2018Chen C. Nguyen B.N. Mitchell G. Margolis S.R. Ma D. Portnoy D.A. The listeriolysin O PEST-like sequence co-opts AP-2-mediated endocytosis to prevent plasma membrane damage during Listeria monocyogenes infection.Cell Host Microbe. 2018; 23 (this issue): 786-795Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar show that a PEST sequence prevents cytotoxicity by mediating LLO endocytosis from the plasma membrane. In order to replicate inside mammalian cells, intracellular bacterial pathogens remodel the host cell plasma membrane and/or endomembrane system (Pizarro-Cerdá et al., 2016Pizarro-Cerdá J. Charbit A. Enninga J. Lafont F. Cossart P. Manipulation of host membranes by the bacterial pathogens Listeria, Francisella, Shigella and Yersinia.Semin. Cell Dev. Biol. 2016; 60: 155-167Crossref PubMed Scopus (27) Google Scholar). Bacterial manipulation of host membranes is often subject to tight temporal and spatial regulation, thereby limiting toxicity to the mammalian cell and ensuring longevity of intracellular bacteria. The Gram-positive bacterium Listeria monocytogenes is an important cause of abortions and meningitis in the immunocompromised (Posfay-Barbe and Wald, 2009Posfay-Barbe K.M. Wald E.R. Listeriosis.Semin. Fetal Neonatal Med. 2009; 14: 228-233Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). After internalization into mammalian cells through a process resembling phagocytosis, L. monocytogenes initially resides in vacuoles derived from the plasma membrane (Schnupf and Portnoy, 2007Schnupf P. Portnoy D.A. Listeriolysin O: a phagosome-specific lysin.Microbes Infect. 2007; 9: 1176-1187Crossref PubMed Scopus (278) Google Scholar). Approximately 30 min after uptake, bacteria perforate vacuoles through the action of the pore-forming toxin Listeriolysin O (LLO). Acting in conjunction with two bacterial phospholipases, LLO mediates the escape of L. monocytogenes into the host cytosol, where bacteria replicate extensively. Cytosolic bacteria spread from infected host cells to neighboring healthy cells through a motility process that involves subversion of the host actin cytoskeleton. This complex intracellular life cycle of L. monocytogenes is thought to provide an environment conducive for bacterial growth and allow protection from the humoral immune response. LLO is essential for virulence and belongs to a family of cholesterol-dependent cytolysins (CDCs) that includes perfringolysin O from Clostridium perfringens, anthrolysin O from Bacillus anthracis, pneumolysin from Streptococcus pneumoniae, and streptolysin O from Streptococcus pyogenes (Schnupf and Portnoy, 2007Schnupf P. Portnoy D.A. Listeriolysin O: a phagosome-specific lysin.Microbes Infect. 2007; 9: 1176-1187Crossref PubMed Scopus (278) Google Scholar). Of all these CDCs, only LLO has evolved to function in vacuoles. The other CDCs all act on the outside of the plasma membrane to mediate lysis of host cells. Importantly, after L. monocytogenes escapes from vacuoles into the cytosol, mechanisms exist to ensure that cytoplasmic LLO does not perforate the host plasma membrane. Perhaps the best-understood mechanism involves inhibition of LLO activity by the neutral pH of the cytoplasm. LLO has a pH optimum of ∼5.5, thereby ensuring activity in vacuoles while limiting activity in the cytosol. Importantly, experiments involving a mutant LLO enzyme that has a neutral pH optimum demonstrate that pH control of LLO limits lysis of host cells, promotes intracellular growth of bacteria, and augments virulence in mice (Glomski et al., 2002Glomski I.J. Gedde M.M. Tsang A.W. Swanson J.A. Portnoy D.A. The Listeria monocytogenes hemolysin has an acidic pH optimum to compartmentalize activity and prevent damage to infected host cells.J. Cell Biol. 2002; 156: 1029-1038Crossref PubMed Scopus (207) Google Scholar). Another means of restricting LLO activity in the cytosol involves a 19-amino PEST-like sequence in the amino terminus of LLO (Decatur and Portnoy, 2000Decatur A.L. Portnoy D.A. A PEST-like sequence in listeriolysin O essential for Listeria monocytogenes pathogenicity.Science. 2000; 290: 992-995Crossref PubMed Scopus (193) Google Scholar). PEST sequences are so named because they often contain the amino acids proline (P), glutamate (E), serine (S), and threonine (T) (Rechsteiner and Rogers, 1996Rechsteiner M. Rogers S.W. PEST sequences and regulation by proteolysis.Trends Biochem. Sci. 1996; 21: 267-271Abstract Full Text PDF PubMed Scopus (1404) Google Scholar). Importantly, removal of the PEST-like sequence from LLO results in damage to the plasma membrane of host cells, inhibition of growth of cytoplasmic bacteria, and a profound attenuation of virulence in mice (Decatur and Portnoy, 2000Decatur A.L. Portnoy D.A. A PEST-like sequence in listeriolysin O essential for Listeria monocytogenes pathogenicity.Science. 2000; 290: 992-995Crossref PubMed Scopus (193) Google Scholar). Interestingly, the PEST-like sequence in LLO is absent from all other CDTs. Appending the PEST sequence of LLO to the amino terminus of streptolysin O (SLO) diminishes cytotoxicity by SLO. In addition, expression of a PEST-SLO chimeric protein partly restores cytoplasmic growth to L. monocytogenes deleted in the gene encoding LLO. Collectively, these results indicate that the PEST-like sequence makes a critical contribution to virulence by limiting LLO activity in the cytosol. However, the mechanism by which this sequence controls LLO has remained elusive. Although PEST sequences have been implicated in proteasome-mediated degradation (Rechsteiner and Rogers, 1996Rechsteiner M. Rogers S.W. PEST sequences and regulation by proteolysis.Trends Biochem. Sci. 1996; 21: 267-271Abstract Full Text PDF PubMed Scopus (1404) Google Scholar), the PEST-like sequence in LLO does not affect protein stability (Schnupf and Portnoy, 2007Schnupf P. Portnoy D.A. Listeriolysin O: a phagosome-specific lysin.Microbes Infect. 2007; 9: 1176-1187Crossref PubMed Scopus (278) Google Scholar). New work by Chen et al., 2018Chen C. Nguyen B.N. Mitchell G. Margolis S.R. Ma D. Portnoy D.A. The listeriolysin O PEST-like sequence co-opts AP-2-mediated endocytosis to prevent plasma membrane damage during Listeria monocyogenes infection.Cell Host Microbe. 2018; 23 (this issue): 786-795Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar in this issue of Cell Host and Microbe makes a major contribution to understanding how the PEST-like sequence controls LLO activity. Collectively, their findings support the idea that the PEST-like sequence restricts LLO cytotoxicity by physically interacting with a critical component of the host endocytic machinery and mediating the removal of LLO from the plasma membrane. Chen et al. found that full-length LLO is present in punctuate structures in the host cytosol that co-localize with ubiquitin and the autophagy adaptor protein p62 (Chen et al., 2018Chen C. Nguyen B.N. Mitchell G. Margolis S.R. Ma D. Portnoy D.A. The listeriolysin O PEST-like sequence co-opts AP-2-mediated endocytosis to prevent plasma membrane damage during Listeria monocyogenes infection.Cell Host Microbe. 2018; 23 (this issue): 786-795Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). By contrast, removal of the PEST-like sequence from LLO causes the protein to accumulate at the plasma membrane of mammalian cells. Studies using total internal reflection fluorescence microscopy (TIRF) revealed that when full-length LLO contacts the plasma membrane, it subsequently rapidly disappears from the membrane. By contrast, LLO lacking the PEST-like sequence was largely retained at the plasma membrane. Taken together, these results suggested that the PEST-like sequence mediates removal of LLO from the plasma membrane. In order to understand how the PEST-like sequence regulates LLO, the yeast two-hybrid system was used to screen a mouse cDNA library with LLO as bait. One of the mouse proteins identified was Ap2a2, also known as α2-adaptin. This protein is a component of the heterotetrameric adaptor protein 2 (AP2), which has a critical role in clathrin-dependent endocytosis (Smith et al., 2017Smith S.M. Baker M. Halebian M. Smith C.J. Weak molecular interactions in clathrin-mediated endocytosis.Front. Mol. Biosci. 2017; 4: 72Crossref PubMed Scopus (21) Google Scholar). AP2 interacts with cargo, endocytic accessory proteins, and clathrin triskelia. In this way, AP2 mediates the assembly of clathrin coats around vesicles containing cargo destined for endocytosis. The known roles of Ap2a2 are to recruit accessory proteins that aid in endocytosis, including amphyphysin, epsin, and Eps15. By performing mutational analysis, Chen et al. demonstrated that the PEST-like sequence in LLO mediates interaction with Ap2a2 in yeast and in mammalian cells. Further experiments demonstrated that Ap2a2 allows efficient intracellular growth of L. monocytogenes by preventing LLO-induced toxicity of host cells. These experiments involved bone-marrow-derived macrophages (BMMs) that were inactivated in the Ap2a2 gene using CRISPR/Cas9 technology. Compared to wild-type BMMs, Ap2a2- macrophages exhibited reduced numbers of viable intracellular L. monocytogenes. In addition, studies involving the DNA stain SYTOX Blue indicated that the host plasma membrane is damaged in infected Ap2a2- BMMs. Importantly, the plasma membrane damage and bacterial growth defect in Ap2a2- BMMs was due to secretion of LLO in the cytoplasm of host cells. This concept was cleverly demonstrated through the use of an L. monocytogenes strain engineered to excise the gene encoding LLO only when bacteria escape to the cytosol. Altogether, the findings indicate that the PEST-like sequence in LLO prevents plasma membrane damage through Ap2a2, presumably by co-opting its endocytic function. Interestingly, PEST sequences are prevalent in eukaryotic G-protein-coupled receptors (GPCRs) (Tovo-Rodrigues et al., 2014Tovo-Rodrigues L. Roux A. Hutz M.H. Rohde L.A. Woods A.S. Functional characterization of G-protein-coupled receptors: a bioinformatics approach.Neuroscience. 2014; 277: 764-779Crossref PubMed Scopus (23) Google Scholar), and emerging evidence suggests that PEST sequences may control trafficking of at least some of these receptors (Zhuang et al., 2012Zhuang X. Northup J.K. Ray K. Large putative PEST-like sequence motif at the carboxyl tail of human calcium receptor directs lysosomal degradation and regulates cell surface receptor level.J. Biol. Chem. 2012; 287: 4165-4176Crossref PubMed Scopus (28) Google Scholar). Remarkably, Chen et al. found that a PEST sequence from the GPCR Human Calcium Receptor (HCaR) can functionally substitute for the LLO PEST-like sequence to control cytotoxicity and virulence. The HCaR PEST sequence interacts with Ap2a2 in a yeast two-hybrid system. Whereas LLO lacking its PEST-like sequence is cytotoxic, LLO fused to the PEST sequence of HCaR (HCaR.PEST-LLO) has greatly reduced toxicity. Finally, compared to L. monocytogenes expressing LLO lacking its PEST-like sequence, bacteria that produce HCaR.PEST-LLO grow more efficiently in BMMs and are more virulent in mice. These results suggest that the PEST sequences from LLO and HCaR have similar cellular targets and functions. Several important questions emerge from the Chen et al. study. First, is it certain that Ap2a2 limits cytotoxicity and allows bacterial growth through the endocytic removal of LLO? Since the only known function of Ap2a2 is in endocytosis (Smith et al., 2017Smith S.M. Baker M. Halebian M. Smith C.J. Weak molecular interactions in clathrin-mediated endocytosis.Front. Mol. Biosci. 2017; 4: 72Crossref PubMed Scopus (21) Google Scholar), this idea seems reasonable. However, the concept has not been directly tested. In future work, it would be informative to perform TIRF studies to determine if removal of LLO from the plasma membrane is compromised in mammalian cells inhibited for Ap2a2 or other proteins involved in endocytosis, such as clathrin or the GTPase Dynamin. Second, does the PEST-like sequence in LLO co-opt a constitutive pathway of endocytosis, or does it stimulate clathrin-mediated uptake? If the PEST-like sequence augments rates of endocytosis, then what is the mechanism of this regulation? Finally, is there a general role for PEST sequences in endocytic trafficking of eukaryotic proteins? Answers to at least some of these questions will undoubtedly be answered by future work on the PEST-like sequence in LLO. The Listeriolysin O PEST-like Sequence Co-opts AP-2-Mediated Endocytosis to Prevent Plasma Membrane Damage during Listeria InfectionChen et al.Cell Host & MicrobeJune 13, 2018In BriefThe intracellular pathogen Listeria produces Listeriolysin O (LLO), a cytolysin. Chen et al. discovered that the PEST-like sequence of LLO interacts with a cellular endocytosis adaptor to promote the endocytosis of plasma membrane-associated LLO, thereby preventing its cytotoxicity to the infected cell. This mechanism is critical for Listeria pathogenesis. Full-Text PDF Open Archive" @default.
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• W2808078136 title "A Helpful PEST for Listeriolysin O?" @default.
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