Abstract
Large bacterial protein toxins autotranslocate functional effector domains to the eukaryotic cell cytosol, resulting in alterations to cellular functions that ultimately benefit the infecting pathogen. Among these toxins, the clostridial glucosylating toxins (CGTs) produced by Gram-positive bacteria and the multifunctional-autoprocessing RTX (MARTX) toxins of Gram-negative bacteria have distinct mechanisms for effector translocation, but a shared mechanism of post-translocation autoprocessing that releases these functional domains from the large holotoxins. These toxins carry an embedded cysteine protease domain (CPD) that is activated for autoprocessing by binding inositol hexakisphosphate (InsP6), a molecule found exclusively in eukaryotic cells. Thus, InsP6-induced autoprocessing represents a unique mechanism for toxin effector delivery specifically within the target cell. This review summarizes recent studies of the structural and molecular events for activation of autoprocessing for both CGT and MARTX toxins, demonstrating both similar and potentially distinct aspects of autoprocessing among the toxins that utilize this method of activation and effector delivery.
Highlights
Pathogenic bacteria frequently export protein toxins that target eukaryotic intracellular proteins to alter host cell function to the benefit of the infectious pathogen
The B component is a protein subunit assembled with the effector (A) subunit within the bacteria before export, while for other toxins, the B and A subunits are exported separately and assembled at the surface of the target cell
Clostridial glucosylating toxins (CGTs), known as large clostridial cytotoxins, are structurally and functionally related toxins produced by different Clostridium sp. that range in size from 250 to 308 kDa and have sequence identity from 26% to 76% [7,8]
Summary
Pathogenic bacteria frequently export protein toxins that target eukaryotic intracellular proteins to alter host cell function to the benefit of the infectious pathogen. Still other toxins are expressed as a single polypeptide that is nicked to separate the A and B domains by endogenous bacterial proteases (such as botulinum toxin [5]) or by host cell proteases during translocation (such as diphtheria toxin [6]). All of these processes succeed in delivering the smaller active effector domains or subunits into the host cell, where they can access their intracellular protein targets. This process represents a novel strategy for toxin activation and subsequent delivery of effectors to target cells
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