Abstract
Bacterial pore-forming toxin aerolysin-like proteins (ALPs) are widely distributed in animals and plants. However, functional studies on these ALPs remain in their infancy. βγ-CAT is the first example of a secreted pore-forming protein that functions to modulate the endolysosome pathway via endocytosis and pore formation on endolysosomes. However, the specific cell surface molecules mediating the action of βγ-CAT remain elusive. Here, the actions of βγ-CAT were largely attenuated by either addition or elimination of acidic glycosphingolipids (AGSLs). Further study revealed that the ALP and trefoil factor (TFF) subunits of βγ-CAT bind to gangliosides and sulfatides, respectively. Additionally, disruption of lipid rafts largely impaired the actions of βγ-CAT. Finally, the ability of βγ-CAT to clear pathogens was attenuated in AGSL-eliminated frogs. These findings revealed a previously unknown double binding pattern of an animal-secreted ALP in complex with TFF that initiates ALP-induced endolysosomal pathway regulation, ultimately leading to effective antimicrobial responses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acidic Glycosphingolipids / antagonists & inhibitors
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Acidic Glycosphingolipids / biosynthesis
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Acidic Glycosphingolipids / chemistry*
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Aeromonas hydrophila / growth & development
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Aeromonas hydrophila / pathogenicity
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Amphibian Proteins / genetics
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Amphibian Proteins / immunology*
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Amphibian Proteins / metabolism
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Animals
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Anura
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Bacterial Toxins / genetics
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Bacterial Toxins / immunology*
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Bacterial Toxins / metabolism
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Ceramides / antagonists & inhibitors
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Ceramides / biosynthesis
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Ceramides / chemistry
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Cerebrosides / antagonists & inhibitors
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Cerebrosides / biosynthesis
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Cerebrosides / chemistry
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Gangliosides / antagonists & inhibitors
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Gangliosides / biosynthesis
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Gangliosides / chemistry
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Gene Expression
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Gram-Negative Bacterial Infections / genetics
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Gram-Negative Bacterial Infections / immunology*
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Gram-Negative Bacterial Infections / microbiology
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Humans
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Interleukin-1beta / biosynthesis
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Lysosomes / drug effects
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Lysosomes / immunology*
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Lysosomes / microbiology
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Membrane Microdomains / drug effects
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Membrane Microdomains / immunology
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Membrane Microdomains / microbiology
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Meperidine / analogs & derivatives
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Meperidine / pharmacology
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Multiprotein Complexes / genetics
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Multiprotein Complexes / immunology*
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Multiprotein Complexes / metabolism
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Pore Forming Cytotoxic Proteins / genetics
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Pore Forming Cytotoxic Proteins / immunology*
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Pore Forming Cytotoxic Proteins / metabolism
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Sphingosine / antagonists & inhibitors
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Sphingosine / biosynthesis
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Sphingosine / chemistry
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THP-1 Cells
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Trefoil Factor-3 / genetics
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Trefoil Factor-3 / immunology*
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Trefoil Factor-3 / metabolism
Substances
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Acidic Glycosphingolipids
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Amphibian Proteins
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Bacterial Toxins
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Ceramides
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Cerebrosides
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Gangliosides
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Interleukin-1beta
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Multiprotein Complexes
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Pore Forming Cytotoxic Proteins
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Trefoil Factor-3
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4-propionyloxy-4-phenyl-N-methylpiperidine
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aerolysin
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Meperidine
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Sphingosine