PMID- 30181275
OWN - NLM
STAT- MEDLINE
DCOM- 20181010
LR  - 20201209
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 38
DP  - 2018 Sep 18
TI  - The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating 
      protein toxins like Clostridium difficile toxins A and B.
PG  - 9580-9585
LID - 10.1073/pnas.1807658115 [doi]
AB  - Various bacterial protein toxins, including Clostridium difficile toxins A (TcdA) 
      and B (TcdB), attack intracellular target proteins of host cells by 
      glucosylation. After receptor binding and endocytosis, the toxins are 
      translocated into the cytosol, where they modify target proteins (e.g., Rho 
      proteins). Here we report that the activity of translocated glucosylating toxins 
      depends on the chaperonin TRiC/CCT. The chaperonin subunits CCT4/5 directly 
      interact with the toxins and enhance the refolding and restoration of the 
      glucosyltransferase activities of toxins after heat treatment. Knockdown of CCT5 
      by siRNA and HSF1A, an inhibitor of TRiC/CCT, blocks the cytotoxic effects of 
      TcdA and TcdB. In contrast, HSP90, which is involved in the translocation and 
      uptake of ADP ribosylating toxins, is not involved in uptake of the glucosylating 
      toxins. We show that the actions of numerous glycosylating toxins from various 
      toxin types and different species depend on TRiC/CCT. Our data indicate that the 
      TRiC/CCT chaperonin system is specifically involved in toxin uptake and essential 
      for the action of various glucosylating protein toxins acting intracellularly on 
      target proteins.
FAU - Steinemann, Marcus
AU  - Steinemann M
AD  - Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of 
      Medicine, University of Freiburg, 79104 Freiburg, Germany.
AD  - Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
FAU - Schlosser, Andreas
AU  - Schlosser A
AD  - Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, 97080 
      Wurzburg, Germany.
FAU - Jank, Thomas
AU  - Jank T
AD  - Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of 
      Medicine, University of Freiburg, 79104 Freiburg, Germany; 
      thomas.jank@pharmakol.uni-freiburg.de Klaus.Aktories@pharmakol.uni-freiburg.de.
FAU - Aktories, Klaus
AU  - Aktories K
AUID- ORCID: 0000-0002-5397-0436
AD  - Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of 
      Medicine, University of Freiburg, 79104 Freiburg, Germany; 
      thomas.jank@pharmakol.uni-freiburg.de Klaus.Aktories@pharmakol.uni-freiburg.de.
AD  - Center for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180904
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Bacterial Proteins)
RN  - 0 (Bacterial Toxins)
RN  - 0 (Enterotoxins)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (tcdA protein, Clostridium difficile)
RN  - 0 (toxB protein, Clostridium difficile)
RN  - EC 3.6.1.- (Chaperonin Containing TCP-1)
SB  - IM
MH  - Animals
MH  - Bacterial Proteins/*metabolism
MH  - Bacterial Toxins/*metabolism
MH  - Chaperonin Containing TCP-1/antagonists & inhibitors/genetics/*metabolism
MH  - Clostridioides difficile/pathogenicity/*physiology
MH  - Cytosol/metabolism
MH  - Enterotoxins/*metabolism
MH  - Fibroblasts
MH  - Gene Knockdown Techniques
MH  - Glycosylation
MH  - HSP90 Heat-Shock Proteins/metabolism
MH  - HeLa Cells
MH  - Host-Pathogen Interactions/*physiology
MH  - Humans
MH  - Mice
MH  - RNA, Small Interfering/metabolism
PMC - PMC6156611
OTO - NOTNLM
OT  - Clostridium difficile toxins
OT  - TRiC/CCT
OT  - chaperonin
OT  - glycosyltransferase toxins
OT  - toxin uptake
COIS- The authors declare no conflict of interest.
EDAT- 2018/09/06 06:00
MHDA- 2018/10/12 06:00
PMCR- 2019/03/18
CRDT- 2018/09/06 06:00
PHST- 2018/09/06 06:00 [pubmed]
PHST- 2018/10/12 06:00 [medline]
PHST- 2018/09/06 06:00 [entrez]
PHST- 2019/03/18 00:00 [pmc-release]
AID - 1807658115 [pii]
AID - 201807658 [pii]
AID - 10.1073/pnas.1807658115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9580-9585. doi: 
      10.1073/pnas.1807658115. Epub 2018 Sep 4.