The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins like
            <i>Clostridium difficile</i>
            toxins A and B

Steinemann, Marcus; Schlösser, Andreas; Jank, Thomas; Aktories, Klaus

doi:10.1073/pnas.1807658115

Cited by 17 publications

(21 citation statements)

References 56 publications

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“… Rodrigues et al ( 2019 ) Toxins that do not require Hsp90/Hsp70/PPIases GT C. difficile TcdA, TcdB - - - n.a. Haug et al ( 2003a ); Kaiser et al ( 2009 , 2012 ); Dmochewitz et al ( 2011 ); Steinemann et al ( 2018 ) MP B. anthracis lethal toxin - - - n.a. Haug et al ( 2003a ); Zornetta et al ( 2010 ); Dmochewitz et al ( 2011 ) ✔ = folding helper is required for cellular uptake n.a.…”

Section: Discussionmentioning

confidence: 99%

Intoxication of mammalian cells with binary clostridial enterotoxins is inhibited by the combination of pharmacological chaperone inhibitors

Ernst

Sailer

Braune

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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Binary enterotoxins Clostridioides difficile CDT toxin, Clostridium botulinum C2 toxin, and Clostridium perfringens iota toxin consist of two separate protein components. The B-components facilitate receptor-mediated uptake into mammalian cells and form pores into endosomal membranes through which the enzymatic active A-components translocate into the cytosol. Here, the A-components ADP-ribosylate G-actin which leads to F-actin depolymerization followed by rounding of cells which causes clinical symptoms. The protein folding helper enzymes Hsp90, Hsp70, and peptidyl-prolyl cis/trans isomerases of the cyclophilin (Cyp) and FK506 binding protein (FKBP) families are required for translocation of A-components of CDT, C2, and iota toxins from endosomes to the cytosol. Here, we demonstrated that simultaneous inhibition of these folding helpers by specific pharmacological inhibitors protects mammalian, including human, cells from intoxication with CDT, C2, and iota toxins, and that the inhibitor combination displayed an enhanced effect compared to application of the individual inhibitors. Moreover, combination of inhibitors allowed a concentration reduction of the individual compounds as well as decreasing of the incubation time with inhibitors to achieve a protective effect. These results potentially have implications for possible future therapeutic applications to relieve clinical symptoms caused by bacterial toxins that depend on Hsp90, Hsp70, Cyps, and FKBPs for their membrane translocation into the cytosol of target cells.

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Section: Discussionmentioning

confidence: 99%

Intoxication of mammalian cells with binary clostridial enterotoxins is inhibited by the combination of pharmacological chaperone inhibitors

Ernst

Sailer

Braune

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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“…It has been reported that CCT4/5 directly interacted with the Clostridium difficile toxins A (TcdA) and B (TcdB). Suppression of CCT5 function by compound HSF1A blocked the cytotoxic effects of TcdA and TcdB [ 44 ]. Based on these, we propose that HSF1A may also have a negative impact on FAdV-4 replication.…”

Section: Discussionmentioning

confidence: 99%

Requirement of Cellular Protein CCT7 for the Replication of Fowl Adenovirus Serotype 4 (FAdV-4) in Leghorn Male Hepatocellular Cells Via Interaction with the Viral Hexon Protein

Gao

Zhao

Duan

et al. 2019

Viruses

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Fowl adenovirus serotype 4 (FAdV-4) causes hepatitis-hydropericardium syndrome (HHS), leading to severe economic losses in the poultry industry. Although the pathogenesis of FAdV-4 infection has caused much attention, the underlying molecular mechanisms remain poorly understood. Here, we identified chaperonin containing TCP-1 subunit eta (CCT7) as an interacting partner of the FAdV-4 capsid protein hexon. We found that ectopic expression of CCT7 in leghorn male hepatocellular (LMH) cells enhanced hexon expression in pRK5-flag-hexon transfected cells. On the contrary, knockdown of cellular CCT7 by RNAi markedly reduced hexon expression in FAdV-4-infected cells and suppressed viral replication. These data suggest that CCT7 is required for FAdV-4 replication and may serve as a potential target for controlling FAdV-4 infection.

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“…Most toxins that need chaperones and PPIases for their uptake are ADP-ribosyltransferases including clostridial binary toxins, DT and PT. Toxins such as C. difficile TcdA and TcdB or the Bacillus anthracis lethal toxin which are not ADP-ribosyltransferases are independent of Hsp90, Cyps and FKBPs for their cellular uptake ( Haug et al., 2003a ; Kaiser et al., 2009 ; Zornetta et al., 2010 ; Dmochewitz et al., 2011 ; Kaiser et al., 2012 ; Steinemann et al., 2018 ). Investigation of fusion toxins as well as artificial transport of isolated enzyme subunits further supported this hypothesis.…”

Section: Common Characteristics Of Chaperone/ppiase-dependent Toxins ...mentioning

confidence: 99%

Requirement of Peptidyl-Prolyl Cis/Trans isomerases and chaperones for cellular uptake of bacterial AB-type toxins

Ernst

2022

Front. Cell. Infect. Microbiol.

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Bacterial AB-type toxins are proteins released by the producing bacteria and are the causative agents for several severe diseases including cholera, whooping cough, diphtheria or enteric diseases. Their unique AB-type structure enables their uptake into mammalian cells via sophisticated mechanisms exploiting cellular uptake and transport pathways. The binding/translocation B-subunit facilitates binding of the toxin to a specific receptor on the cell surface. This is followed by receptor-mediated endocytosis. Then the enzymatically active A-subunit either escapes from endosomes in a pH-dependent manner or the toxin is further transported through the Golgi to the endoplasmic reticulum from where the A-subunit translocates into the cytosol. In the cytosol, the A-subunits enzymatically modify a specific substrate which leads to cellular reactions resulting in clinical symptoms that can be life-threatening. Both intracellular uptake routes require the A-subunit to unfold to either fit through a pore formed by the B-subunit into the endosomal membrane or to be recognized by the ER-associated degradation pathway. This led to the hypothesis that folding helper enzymes such as chaperones and peptidyl-prolyl cis/trans isomerases are required to assist the translocation of the A-subunit into the cytosol and/or facilitate their refolding into an enzymatically active conformation. This review article gives an overview about the role of heat shock proteins Hsp90 and Hsp70 as well as of peptidyl-prolyl cis/trans isomerases of the cyclophilin and FK506 binding protein families during uptake of bacterial AB-type toxins with a focus on clostridial binary toxins Clostridium botulinum C2 toxin, Clostridium perfringens iota toxin, Clostridioides difficile CDT toxin, as well as diphtheria toxin, pertussis toxin and cholera toxin.

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The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins like Clostridium difficile toxins A and B

Cited by 17 publications

References 56 publications

Intoxication of mammalian cells with binary clostridial enterotoxins is inhibited by the combination of pharmacological chaperone inhibitors

Intoxication of mammalian cells with binary clostridial enterotoxins is inhibited by the combination of pharmacological chaperone inhibitors

Requirement of Cellular Protein CCT7 for the Replication of Fowl Adenovirus Serotype 4 (FAdV-4) in Leghorn Male Hepatocellular Cells Via Interaction with the Viral Hexon Protein

Requirement of Peptidyl-Prolyl Cis/Trans isomerases and chaperones for cellular uptake of bacterial AB-type toxins

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