Killer Toxin K28 resistance in yeast relies on COG complex mediated trafficking of the defence factor Ktd1.

A/B toxins are a diverse family of protein toxins that enter host cells via endocytosis and induce cell death. In yeast, the A/B toxin K28 is internalised to endosomes of susceptible yeast, before following the retrograde trafficking pathway and ultimately triggering cell cycle arrest. The endolysosomal defence factor Ktd1 protects against K28, but its regulation remains unclear. We show all lobe B subunits of the conserved oligomeric Golgi (COG) tethering complex are required for K28 resistance. Our experiments suggest the hypersensitivity of cog mutants is primarily explained by defects in Ktd1 trafficking. Ktd1 mis-localisation in cog mutants is reminiscent to disruptions in Snc1, a surface cargo that recycles multiple times via the Golgi. This work suggests not only that the COG complex is responsible for the precise trafficking of Ktd1 required to mediate toxin defence, but that Ktd1 may survey endolysosomal compartments for toxin. This work underpins the importance of Ktd1 in defence against the A/B toxin K28, and implies how various membrane trafficking regulators could influence toxin effects in other eukaryotic systems.