Vibrio, Aeromonas & Plesiomonas - ppt download

Classes of Bacterial

Bacteria / March 14, 2019

Toxin production by pathogenic microorganisms likely serves to (i) protect against phagocytosis by predatory cells, (ii) aid in penetrating tissue barriers, (iii) promote nutrient release, or (iv) alter cellular architecture and metabolism in ways that facilitate the establishment of a niche for colonization and replication. Useful enzymatic targets for some bacterial toxins may be similar between prokaryotic and eukaryotic environments, necessitating a need for eukaryotic-specific cofactors to regulate toxin activity. Host cell—derived factors may impart localization properties to an effector, induce folding events, provide a platform for the inhibition of cellular processes or support greater substrate promiscuity. The aim of this review is to describe the diversity of bacterial effectors known to require, or to be stimulated by eukaryotic cofactors and to integrate new ideas regarding the structural and functional implications of this relationship.

Fig 1. Examples of cofactor regulation of secreted bacterial enzymes.

Toxins delivered to their target cell by either direct injection (yellow) or cell surface binding and translocation (green) can be host cofactor activated. These enzymes generally contain dynamic structures that assume a catalytically active fold upon complex formation with a host factor. The key depicts this process through cofactor-mediated organization (blue) of an unstructured sequence. Apo, the apoenzyme catalytically-inactive state. Holo, the holoenzyme active state in which the toxin is in complex with its cofactor. CyaA, the plasma membrane-localized nucleotide cyclase toxin from Bordetella pertussis complexed to calcium ions and calmodulin. EF, edema factor from Bacillus anthracis, binds to calmodulin in a different orientation than CyaA. PA, protective antigen. The cofactor for cholera toxin (ARF) is shown in the myristolated, GTP-bound form. ER, endoplasmic reticulum, with cholera toxin peptide being secreted through ER protein channels.

I. Phospholipases

Many bacterial toxins contain catalytic domains with homology to plant patatins, which are lipid acyl hydrolases found in potato tubers. Cofactor activation of phospholipase activity is best characterized for ExoU, a lipid membrane—hydrolyzing protein encoded by the opportunistic pathogen P. aeruginosa. Monoubiquitin, ubiquitin polymers, and ubiquitylated proteins are capable of activating ExoU . Bioinformatic analyses identified at least 17 additional bacterial patatin-like phospholipases that fit the criteria for ubiquitin-mediated activation . Functional studies of a selected subset of enzymes demonstrated that ubiquitin activates phospholipases from P. asymbiotica, B. thailandensis, and P. fluorescens .

ExoU orthologs are also found in frank pathogens within the Rickettsiae, Legionellae, and Salmonellae. R. typhus encodes ExoU homologs, Pat1 and Pat2 [, ]. Both proteins are activated by preparations of bovine SOD1 (bSOD1 [, ]), which may provide a source of ubiquitin . Additionally, R. prowazekii, the etiologic agent of typhus, displays enhanced enzymatic activity in the presence of bSOD1 (ubiquitin, ). Rickettsial-derived PLA enzymes function in cellular entry , phagosomal escape, and noncytolytic free fatty acid release .

VipD lipase from L. pneumophila displays a Rab5-dependent PLA1 activity that targets the enzyme to endosomes resulting in inhibition of phagosome maturation. SseJ, a glycerophospholipid-cholesterol acyltransfersase (GCAT)-like enzyme from Salmonella, is activated by GTP-RhoA likely for the temporal regulation of cholesterol metabolism in infected cells . The Y. enterocolitica homolog to SseJ, YspM, may have a similar function .

II. Transferases

Most cofactor-stimulated transferases catalyze the transfer of an ADP-ribose moiety from nicotinamide adenine dinucleotide to a target protein. Exoenzyme S from P. aeruginosa was one of the first identified bacterial ADP-ribosyltransferases requiring a cofactor for activation . Members of the 14-3-3 family of eukaryotic scaffolding proteins stimulate ADP-ribosylation of a variety of targets causing disruptions in cytoskeletal integrity and vesicular trafficking . Homologous enzymes are present in A. hydrophila and V. parahaemolyticus .

Another enzyme from P. aeruginosa, ExoT, is similar (76% identity) to ExoS and requires 14-3-3 proteins as cofactors, but has limited target recognition and is not overtly cytotoxic . CrkI and CrkII are the only proteins modified by ExoT . ADP-ribosylation uncouples integrin signaling and alters the cytoskeleton. A. hydrophila and A. salmonicida encode enzymes similar to ExoT/S termed AexT .

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