The ERM Proteins Ezrin and Moesin Regulate Retrograde Shiga Toxin Transport

Synopsis Ezrin and moesin depletion leads to reduced binding of Shiga toxin (Stx), reduced retrograde Stx transport to the Golgi and protection from Stx toxicity. Endocytosed toxin seems to be arrested in hybrid compartments between early and late endosomal stages unable to recruit the retromer complex. Vps11 depletion on the other hand, leads to increased retrograde Stx transport. Finally, ezrin and moesin knockdown does not affect retrograde transport of ricin. The ERM proteins (ezrin, radixin and moesin) are known for connecting the actin cytoskeleton to the plasma membrane. They have been found to associate with lipid rafts as well as to be important for endosomal sorting and receptor signaling. However, little is known about the role of ERM proteins in retrograde transport and lipid homeostasis. In this study, we show that ezrin and moesin are important for efficient cell surface association of Shiga toxin (Stx) as well as for its retrograde transport. Furthermore, we show that depletion of these proteins influences endosomal dynamics and seems to enhance Stx transport toward lysosomes. We also show that knockdown of Vps11, a subunit of the HOPS complex, leads to increased retrograde Stx transport and reverses the inhibiting effect of ezrin and moesin knockdown. Importantly, retrograde transport of the plant toxin ricin, which binds to both glycolipids and glycoproteins with a terminal galactose, seems to be unaffected by ezrin and moesin depletion.