Cross Kingdom Activators of Five Classes of Bacterial Effectors.

Abstract

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 (Fig 1). 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 (Table 1). Fig 1 Examples of cofactor regulation of secreted bacterial enzymes. Table 1 Cross kingdom enzyme stimulators for secreted bacterial toxins. 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 [1]. Bioinformatic analyses identified at least 17 additional bacterial patatin-like phospholipases that fit the criteria for ubiquitin-mediated activation [2]. Functional studies of a selected subset of enzymes demonstrated that ubiquitin activates phospholipases from P. asymbiotica, B. thailandensis, and P. fluorescens [2]. ExoU orthologs are also found in frank pathogens within the Rickettsiae, Legionellae, and Salmonellae. R. typhus encodes ExoU homologs, Pat1 and Pat2 [3,4]. Both proteins are activated by preparations of bovine SOD1 (bSOD1 [3,4]), which may provide a source of ubiquitin [1]. Additionally, R. prowazekii, the etiologic agent of typhus, displays enhanced enzymatic activity in the presence of bSOD1 (ubiquitin, [5]). Rickettsial-derived PLA enzymes function in cellular entry [6], phagosomal escape, and noncytolytic free fatty acid release [7]. VipD lipase from L. pneumophila displays a Rab5-dependent PLA1 activity [8] 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 [9] likely for the temporal regulation of cholesterol metabolism in infected cells [10]. The Y. enterocolitica homolog to SseJ, YspM, may have a similar function [11].