Abstract
Repeats-in-toxin (RTX) exoproteins of Gram-negative bacteria form a steadily growing family of proteins with diverse biological functions. Their common feature is the unique mode of export across the bacterial envelope via the type I secretion system and the characteristic, typically nonapeptide, glycine- and aspartate-rich repeats binding Ca2+ ions. In this review, we summarize the current state of knowledge on the organization of rtx loci and on the biological and biochemical activities of therein encoded proteins. Applying several types of bioinformatic screens on the steadily growing set of sequenced bacterial genomes, over 1000 RTX family members were detected, with the biological functions of most of them remaining to be characterized. Activities of the so far characterized RTX family members are then discussed and classified according to functional categories, ranging from the historically first characterized pore-forming RTX leukotoxins, through the large multifunctional enzymatic toxins, bacteriocins, nodulation proteins, surface layer proteins, up to secreted hydrolytic enzymes exhibiting metalloprotease or lipase activities of industrial interest.
Highlights
With molecular cloning and DNA sequencing taking grounds in bacteriology labs, it has become clear since 1987 that a novel family of large secreted cytolytic toxins of Gramnegative pathogens emerged
Pore-forming RTX cytotoxins represent a unique class of bacterial proteins that share (1) the requirement for posttranslational activation through amide-linked fatty acylation of internal lysine residues; (2) possess a hydrophobic domain that was shown or is presumed to form cationselective pores in target cell membranes; (3) are exported by type I secretion system (TISS); and (4) upon secretion are activated for exerting biological activity by binding calcium ions within the acidic glycine- and aspartate-rich nonapeptide repeats
This was corroborated by demonstrating that pore-forming RTX toxins, such as M. haemolytica LktA, A. actinomycetemcomitans leukotoxins of A. actinomycetemcomitans (LtxA) or B. pertussis cyclase (AC) toxin (CyaA), caused unregulated calcium influx into target cells (Taichman et al, 1991b; Sun et al, 1999; Fiser et al, 2007)
Summary
With molecular cloning and DNA sequencing taking grounds in bacteriology labs, it has become clear since 1987 that a novel family of large secreted cytolytic toxins of Gramnegative pathogens emerged. Pore-forming RTX cytotoxins represent a unique class of bacterial proteins that share (1) the requirement for posttranslational activation through amide-linked fatty acylation of internal lysine residues; (2) possess a hydrophobic domain that was shown or is presumed to form cationselective pores in target cell membranes; (3) are exported by TISSs; and (4) upon secretion are activated for exerting biological activity by binding calcium ions within the acidic glycine- and aspartate-rich nonapeptide repeats. The initial observation that HlyA of E. coli was responsible for significant calcium influx into cells was made by Jorgensen et al (1983) This was corroborated by demonstrating that pore-forming RTX toxins, such as M. haemolytica LktA, A. actinomycetemcomitans LtxA or B. pertussis CyaA, caused unregulated calcium influx into target cells (Taichman et al, 1991b; Sun et al, 1999; Fiser et al, 2007). A further nine putative RTX proteins appear to exhibit weak homology to Hedgehog/ Intein domain proteins, suggesting that they might undergo autoprocessing and splicing
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