Hijacking Multivesicular Bodies Enables Long-Term and Exosome-Mediated Long-Distance Action of Anthrax Toxin

Abrami, Laurence; Brandi, Lucia; Moayeri, Mahtab; Brown, Michael; Krantz, Bryan A.; Leppla, Stephen H.; Goot, F. Gisou van der

doi:10.1016/j.celrep.2013.10.019

Cited by 180 publications

(146 citation statements)

References 36 publications

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“…Although the release of endocytosed toxins back into the extracellular medium has been previously described for the plant toxin ricin (88)(89)(90) and for anthrax toxin (91), neither of those toxins has been reported to follow the endocytic recycling route (91,92). The release of endocytosed ricin seems to occur through a mechanism involving exocytosis of multivesicular bodies (89), allowing intoxication of bystander cell populations (90).…”

Section: Discussionmentioning

confidence: 99%

“…The release of endocytosed ricin seems to occur through a mechanism involving exocytosis of multivesicular bodies (89), allowing intoxication of bystander cell populations (90). In the case of anthrax, it has been demonstrated that the toxin is delivered into the extracellular medium in exosomes, contributing to prolonged toxicity and possibly to transmission of the toxin to distant cells (91). During this work, several attempts were made to detect activity of recycled AIP56.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular Trafficking of AIP56, an NF-κB-Cleaving Toxin from Photobacterium damselae subsp. piscicida

et al. 2014

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f AIP56 (apoptosis-inducing protein of 56 kDa) is a metalloprotease AB toxin secreted by Photobacterium damselae subsp. piscicida that acts by cleaving NF-B. During infection, AIP56 spreads systemically and depletes phagocytes by postapoptotic secondary necrosis, impairing the host phagocytic defense and contributing to the genesis of infection-associated necrotic lesions. Here we show that mouse bone marrow-derived macrophages (mBMDM) intoxicated by AIP56 undergo NF-B p65 depletion and apoptosis. Similarly to what was reported for sea bass phagocytes, intoxication of mBMDM involves interaction of AIP56 C-terminal region with cell surface components, suggesting the existence of a conserved receptor. Biochemical approaches and confocal microscopy revealed that AIP56 undergoes clathrin-dependent endocytosis, reaches early endosomes, and follows the recycling pathway. Translocation of AIP56 into the cytosol requires endosome acidification, and an acidic pulse triggers translocation of cell surface-bound AIP56 into the cytosol. Accordingly, at acidic pH, AIP56 becomes more hydrophobic, interacting with artificial lipid bilayer membranes. Altogether, these data indicate that AIP56 is a short-trip toxin that reaches the cytosol using an acidic-pH-dependent mechanism, probably from early endosomes. Usually, for short-trip AB toxins, a minor pool reaches the cytosol by translocating from endosomes, whereas the rest is routed to lysosomes for degradation. Here we demonstrate that part of endocytosed AIP56 is recycled back and released extracellularly through a mechanism requiring phosphoinositide 3-kinase (PI3K) activity but independent of endosome acidification. So far, we have been unable to detect biological activity of recycled AIP56, thereby bringing into question its biological relevance as well as the importance of the recycling pathway.A IP56 (apoptosis-inducing protein of 56 kDa) is a plasmidencoded toxin of Photobacterium damselae subsp. piscicida (1), a Gram-negative bacterium that infects economically important fish species (2, 3) and is considered one of the most relevant pathogens in mariculture (2-5). In acute infections, a rapid septicemia develops, causing very high mortalities (2, 4, 6). Histopathological analysis of the diseased animals revealed cytotoxic alterations (4, 7-10) that were found to result from pathogeninduced apoptotic death of macrophages and neutrophils (11) and later associated with the activity of AIP56 (1). Indeed, it has been shown that in infected fish, the toxin is systemically distributed and depletes macrophages and neutrophils by postapoptotic secondary necrosis (12), leading to the impairment of the phagocytic defense of the host and consequently favoring P. damselae subsp. piscicida survival and dissemination. Furthermore, the occurrence of a secondary necrotic process in which the phagocytes undergoing apoptosis lyse and release their cytotoxic contents contributes to the genesis of the infection-associated necrotic lesions (12, 13). These observations, together with the fac...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intracellular Trafficking of AIP56, an NF-κB-Cleaving Toxin from Photobacterium damselae subsp. piscicida

et al. 2014

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“…anthracis virulence factor, is translocated into the lumen of endosomal intraluminal vesicles (ILVs), persists in them for days and can be transmitted to neighboring cells [15]. Trichosanthin (TCS), a plant toxin, is incorporated into intraluminal vesicles of the MVB and is then secreted in association with exosomes upon fusion of the MVB with the plasma membrane [16].…”

Section: Introductionmentioning

confidence: 99%

Cell Propagation of Cholera Toxin CTA ADP-Ribosylating Factor by Exosome Mediated Transfer

Zanetti¹,

Gallina²,

Fabbri³

et al. 2018

Preprint

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Abstract:Here we first report, how cholera toxin (CT) A subunit (CTA), the bacterial enzyme moiety responsible of cell signaling alteration, can take over the exosomal pathway, spread extracellularly and be transmitted in a cell population. A first evidence for long-term transmission of CT toxic effect via extracellular vesicles was obtained in CHO cells. To follow CT intracellular route towards exosome secretion we adopted a strategy apt to convert multivesicular body (MVB) derived exosomes in traceable fluorescent vectors. CT treated Me665 cells, a human melanoma cell line highly expressing caveolin-1 (Cav-1) and GM1, were used to purify and characterize fluorescent

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“…In particular, LF can be transported not only into the cytosol but also into the lumen of endosomal intraluminal vesicles. The vesicles fully protect LF from proteolytic degradation and significantly later fuse and release LF into the cytosol [114]. These findings may indicate that the focus of anthrax antitoxin research should be shifted toward LF.…”

Section: Polyvalent Cationic Pore Blockersmentioning

confidence: 98%

Inhibitors of pore-forming toxins

Bezrukov

Nestorovich

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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Hijacking Multivesicular Bodies Enables Long-Term and Exosome-Mediated Long-Distance Action of Anthrax Toxin

Cited by 180 publications

References 36 publications

Intracellular Trafficking of AIP56, an NF-κB-Cleaving Toxin from Photobacterium damselae subsp. piscicida

Intracellular Trafficking of AIP56, an NF-κB-Cleaving Toxin from Photobacterium damselae subsp. piscicida

Cell Propagation of Cholera Toxin CTA ADP-Ribosylating Factor by Exosome Mediated Transfer

Inhibitors of pore-forming toxins

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