Bacterial protein toxins and lipids: role in toxin targeting and activity

Abstract

All bacterial toxins, which globally are hydrophilic proteins, interact first with their target cells by recognizing a surface receptor, which is either a lipid or a lipid derivative, or another compound but in a lipid environment. Intracellular active toxins follow various trafficking pathways, the sorting of which is greatly dependent on the nature of the receptor, notably lipidic receptor or receptor embedded into a distinct environment such as lipid microdomains. Numerous other toxins act locally on cell membrane. Indeed, phospholipase activity is a common mechanism shared by several membrane‐damaging toxins. In addition, many toxins active intracellularly or on cell membrane modulate host cell phospholipid pathways. Unusually, a few bacterial toxins require a lipid post‐translational modification to be active. Thereby, lipids are obligate partners of bacterial toxins.

Treponema denticola Major Outer Sheath Protein Impairs the Cellular Phosphoinositide Balance That Regulates Neutrophil Chemotaxis

“…For example, it has been reported that Msp interacts with at least one cell surface protein of 65-kDa in HeLa epithelial cells [49], although this protein or other putative receptors have yet to be identified in neutrophils or characterized further. Many bacterial protein toxins are able to interfere with host lipid metabolism including modifying the activity of lipid phosphatases and kinases [50]. Our findings presented here extend this knowledge and indicate that Msp is a novel protein that can modulate activity of PI3-kinase and the lipid phosphatase PTEN, as a pathogenic mechanism to modulate downstream cell-signaling pathways leading to impairment of crucial host cell functions.…”

Old and new adjuvants

“…Von Behring and others found that immunization with these (at the time rather impure) proteins protected animals against the disease they induced and that antisera produced against them in, for example, horses, was also protective upon transfer into intoxicated hosts [9]. To protect against intoxication by these proteins, they were sometimes given with the antisera but later Glenny and Sudmersen and Ramon [10,11] realized that the toxins could be inactivated with formaldehyde and were still sufficient to induce antibody production without toxic sequelae [12]. The consequent demand for anti-toxin antibodies led to large scale immunization of horses for production of such antisera and memorable events such as the transport of life saving diphtheria anti-toxin to Nome in 1925.…”

Intoxication of epithelial cells by plasmid-encoded toxin requires clathrin-mediated endocytosis

“…Interestingly, Pet is not an AB toxin because: (i) it does not fit into this standard model of ABtoxin trafficking, since it does not dissociate into component parts in the ER, but can be found in the cytosol as an intact 104 kDa protein; (ii) the arginineoverlysine codon bias is not found in Pet; this codon bias is thought protect the translocated A chain from ubiquitindependent proteasomal degradation, since ubiquitin is appended to lysine residues (Hazes & Read, 1997); (iii) Pet lacks a C-terminal KDEL or RDEL ER retrieval motif, so its retrograde transport to the ER may occur by a COP-1-independent mechanism, such as that observed for Shiga toxin and ricin (Chen et al, 2003;Girod et al, 1999). Furthermore, transport of CT from the plasma membrane to Golgi is mainly mediated by endosomes containing caveolin-1, and is independent of clathrin-coated pits (Nichols, 2002), and it is thought that lipid rafts are needed for toxin sorting in intracellular trafficking pathways (Geny & Popoff, 2006). However, as showed here, Pet is taken up by clathrin-dependent endocytosis, and depletion of cholesterol does not affect either its internalization or its retrograde transport.…”