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. 2022 Jan 16;14(1):62. doi: 10.3390/toxins14010062

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Modes of action of selection toxins from AB₅ toxin families. (A) Pertussis toxin family: ArtA acts as an ADP ribosyltransferase and, after cleavage from ArtB at the endoplasmic reticulum (ER), targets α-subunits of G proteins in the host cell cytosol (1a), leading to an increase of intracellular cAMP levels. The increase in cAMP concentration affects fluid secretion pathways and causes diarrhea. ArtA can also elevate insulin secretion, causing insulinemia (1b); (B) Cholera toxin family: LT-I/II targets and activates adenylyl cyclase in epithelial cells, causing an increase in intracellular cAMP concentrations. Elevated cAMP levels stimulate PKA-dependent pathways, creating an imbalance of fluid and chloride ions. Secretion of fluid and electrolytes ultimately results in watery diarrhea and severe dehydration; (C) Subtilase cytotoxin: Following cleavage from SubB at the ER, SubA targets and cleaves the ER chaperone protein BiP/GRP78, leading to an accumulation of unfolded proteins. The increased concentration of unfolded proteins initiates an ER stress response, but BiP/GRP78 cleavage prevents homeostasis restoration in the ER and inhibits the unfolded protein response. This leads to protein synthesis inhibition and apoptosis; (D) Shiga toxin family: Delivery of Stx to the ER leads to an accumulation of unfolded proteins, causing stress in the ER and apoptosis of affected cells. Stx can also cleave an adenine residue of 28S rRNA of the 60S ribosomal subunit, preventing aminoacyl tRNA from binding and stopping protein synthesis. Affected ribosomes undergo a ribotoxic stress response and apoptosis, causing damage to colon, central nervous system (CNS), and kidney cells. Additionally, Stx induces a pro-inflammatory response by signaling cytokines, leukocytes, and the release of reactive oxygen metabolites, which can lead to severe clinical manifestations such as thrombotic thrombocytopenia purpura (TTP), end-stage renal disease, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Created in BioRender.com.

Modes of action of selection toxins from AB₅ toxin families. (A) Pertussis toxin family: ArtA acts as an ADP ribosyltransferase and, after cleavage from ArtB at the endoplasmic reticulum (ER), targets α-subunits of G proteins in the host cell cytosol (1a), leading to an increase of intracellular cAMP levels. The increase in cAMP concentration affects fluid secretion pathways and causes diarrhea. ArtA can also elevate insulin secretion, causing insulinemia (1b); (B) Cholera toxin family: LT-I/II targets and activates adenylyl cyclase in epithelial cells, causing an increase in intracellular cAMP concentrations. Elevated cAMP levels stimulate PKA-dependent pathways, creating an imbalance of fluid and chloride ions. Secretion of fluid and electrolytes ultimately results in watery diarrhea and severe dehydration; (C) Subtilase cytotoxin: Following cleavage from SubB at the ER, SubA targets and cleaves the ER chaperone protein BiP/GRP78, leading to an accumulation of unfolded proteins. The increased concentration of unfolded proteins initiates an ER stress response, but BiP/GRP78 cleavage prevents homeostasis restoration in the ER and inhibits the unfolded protein response. This leads to protein synthesis inhibition and apoptosis; (D) Shiga toxin family: Delivery of Stx to the ER leads to an accumulation of unfolded proteins, causing stress in the ER and apoptosis of affected cells. Stx can also cleave an adenine residue of 28S rRNA of the 60S ribosomal subunit, preventing aminoacyl tRNA from binding and stopping protein synthesis. Affected ribosomes undergo a ribotoxic stress response and apoptosis, causing damage to colon, central nervous system (CNS), and kidney cells. Additionally, Stx induces a pro-inflammatory response by signaling cytokines, leukocytes, and the release of reactive oxygen metabolites, which can lead to severe clinical manifestations such as thrombotic thrombocytopenia purpura (TTP), end-stage renal disease, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Created in BioRender.com.