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The Chaperonin TRiC/CCT Inhibitor HSF1A Protects Cells from Intoxication with Pertussis Toxin

Jinfang Jia1, Manuel Zoeschg1, Holger Barth1

  • 1Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, Germany.

Toxins
|January 22, 2024
PubMed

Insights

The chaperonin TRiC/CCT inhibitor, HSF1A, protects cells from pertussis toxin (PT) by reducing its ADP-ribosylation activity. This study reveals a novel interaction and suggests HSF1A as a therapeutic strategy against whooping cough.

Area of Science:

  • Microbiology
  • Cellular Biology
  • Toxicology

Background:

  • Pertussis toxin (PT) from *Bordetella pertussis* causes whooping cough.
  • The chaperonin TRiC/CCT complex is crucial for protein folding and homeostasis.
  • TRiC/CCT is implicated in the activity of other bacterial toxins like *Clostridioides difficile* TcdB.

Purpose of the Study:

  • To investigate the protective effects of the TRiC/CCT inhibitor HSF1A against PT-induced cell intoxication.
  • To elucidate the mechanism by which HSF1A confers protection against PT.
  • To explore potential therapeutic applications of HSF1A for pertussis.

Main Methods:

  • Treatment of cells with PT and HSF1A.
  • Assay for ADP-ribosylated Gαi levels.
  • In vitro enzyme activity and cellular binding assays for PT.
  • Investigation of PTS1 interaction with CCT5.
  • Measurement of cAMP signaling pathways.

Main Results:

  • HSF1A significantly reduced ADP-ribosylated Gαi levels in PT-treated cells.
  • HSF1A did not affect PT's enzymatic activity or cellular binding.
  • A novel interaction between PTS1 and CCT5 was identified, with reduced signaling upon HSF1A treatment.
  • HSF1A mitigated PT-induced disruptions in cellular cAMP signaling.

Conclusions:

  • HSF1A demonstrates protective effects against pertussis toxin-induced cellular damage.
  • The findings suggest a novel mechanism involving TRiC/CCT and PTS1 in PT intoxication.
  • HSF1A represents a potential therapeutic lead for combating pertussis toxin pathogenicity.

Keywords:
AB-type toxinTRiC/CCTcellular uptakechaperoninpertussis toxintoxin inhibitor

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