Repeats-in-Toxin (RTX) Toxins: A Review

Abstract

Repeats-in-toxin (RTX) exoproteins of Gram-negative bacteria form a steadily growing family ofproteins with diverse biological functions. All the diverse RTX toxins share two common features: (i) they are secreted by a single-step export mechanism via the type I secretion system that employs a “channel–tunnel” conduit spanning across the entire Gram-negative bacterial envelope, thus connecting bacterial cytoplasm to extracellular environment; (ii) RTX toxins possess the characteristic glycine- and aspartate-rich repeats that bind numerous calcium ions, typically in the carboxy-terminal portions ofthe molecule, with the large multifunctional autoprocessing RTX (MARTX) toxins bearing similar repeats also as N-terminal segments. RTX toxins further require physiologically high (>1 mM) Ca2+ concentration for proper folding and biological activity on host epithelial or phagocytic cells. Members of the RTX family of toxins act as effective “contact weapons” and have been shown to play a major role in virulence of a broad range of Gram-negative pathogens. The classical RTX toxins, originally classified as leukotoxins and hemolysins, were shown to penetrate and permeabilize host cell membranes. Research over the past decade, however, revealed that RTX toxins can exert numerous additional activities contributing to cytotoxic action in pathogenesis and virulence of bacterial infections. Some of the RTX toxins affect host cell signaling via uncontrolled conversion ofATP to a key signaling molecule, cAMP (CyaA, MARTXVc), or via interaction with small GTPases (MARTXVc,MARTXVv) and thus effectively subvert host cell physiology. Other RTX toxins induce cytoskeletal rearrangements via covalent cross-linking ofactin molecules (MARTXVc, MARTXVv), or inflict an apoptotic/lytic program on target phagocytic or epithelial cells (HlyA, CyaA, MARTXVv), thereby promoting disease pathogenesis.