Abstract
Protease domains within toxins typically act as the primary effector domain within target cells. By contrast, the primary function of the cysteine protease domain (CPD) in Multifunctional Autoprocessing RTX-like (MARTX) and Clostridium sp. glucosylating toxin families is to proteolytically cleave the toxin and release its cognate effector domains. The CPD becomes activated upon binding to the eukaryotic-specific small molecule, inositol hexakisphosphate (InsP6), which is found abundantly in the eukaryotic cytosol. This property allows the CPD to spatially and temporally regulate toxin activation, making it a prime candidate for developing anti-toxin therapeutics. In this review, we summarize recent findings related to defining the regulation of toxin function by the CPD and the development of inhibitors to prevent CPD-mediated activation of bacterial toxins.
Highlights
Protease domains within toxins typically act as the primary effector domain within target cells
While the specificity of these inhibitors in complex mixtures still needs to be assessed, these results strongly suggest that cysteine protease domain (CPD) inhibitors can prevent the autoproteolytic activation of Multifunctional Autoprocessing RTX-like (MARTX) toxins inside target cells
Analyses of V. cholerae MARTX toxin will likely be transferable to other MARTX toxins, which typically contain Rho Inactivating Domain (RID), actin crosslinking domain (ACD), and/or / domains
Summary
Many bacterial toxins whose targets are within host cells require proteolytic activation for their function. Whereas most toxins, such as cholera toxin and anthrax toxin, are cleaved by a eukaryotic cell protease, a subset of bacterial toxins is autoproteolytically activated by an internal cysteine protease domain (CPD). Toxins 2010, 2 inositol hexakisphosphate (InsP6), the CPD acts as a biosensor that appears to allow for temporal and spatial regulation of toxin activation. Once toxins translocate across eukaryotic cell membranes, the CPD binds to InsP6 within the cell (KD ~ 1–2 μM) [3,4,5] and induces toxin autoprocessing. InsP6 is found at concentrations between 5–100 μM within the cytosol of mammalian cells, exhibits a long half-life in cells, and may be localized to cellular membranes and the nucleus [10,11,12]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
