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

Anthrax lethal toxin is a classical AB toxin comprised of two components: protective antigen (PA) and lethal factor (LF). Here, we show that following assembly and endocytosis, PA forms a channel that translocates LF, not only into the cytosol, but also into the lumen of endosomal intraluminal vesicles (ILVs). These ILVs can fuse and release LF into the cytosol, where LF can proteolyze and disable host targets. We find that LF can persist in ILVs for days, fully sheltered from proteolytic degradation, both in vitro and in vivo. During this time, ILV-localized LF can be transmitted to daughter cells upon cell division. In addition, LF-containing ILVs can be delivered to the extracellular medium as exosomes. These can deliver LF to the cytosol of naive cells in a manner that is independent of the typical anthrax toxin receptor-mediated trafficking pathway, while being sheltered from neutralizing extracellular factors of the immune system. [Display omitted] •Anthrax LT is delivered to the lumen of intraluminal vesicles of endosomes•This localization allows the long-term delivery to the cytosol, for days•This localization also allows LT release into the extracellular space through exosomes•LF-loaded exosomes are engulfed by naive recipient cells allowing long-term action van der Goot and colleagues find that, thanks to the anthrax toxin translocation subunit, the lethal factor is encapsulated into intraluminal vesicles of multivesicular endosomes, where it can remain sheltered from degradation for days. From there it can be delivered to the cytosol, where it can cleave its targets days after entering the cell, or even delivered to the extracellular environment as exosomes to be taken up by distance cells.