GP63 Alters the Macrophage Golgin160-Associated PIST Distribution by Reducing Caspase-3 Expression during <i>Leishmania major</i> Infection

<i>Leishmania major</i>, an intracellular protozoan parasite, resides within parasitophorous vacuoles in host macrophages and relies on host-pathway manipulation for survival. Here, we uncover a novel role of the <i>Leishmania</i> surface metalloprotease GP63 in stabilizing the parasitophorous vacuoles through targeted subversion of host vesicular trafficking and apoptosis. We demonstrate that GP63 is essential for the selective recruitment of the Golgi-associated adaptor protein PIST to the parasitophorous vacuoles, a process that is impaired in GP63-deficient (LmGP63^-/-) parasites. GP63 facilitates PIST-Golgin160 complex formation by suppressing caspase-3 activation, preventing Golgin160 cleavage. Caspase inhibition via Z-VAD-FMK further enhances this complex's recruitment. Moreover, GP63 selectively modulates autophagy by promoting PIST-Beclin1 colocalization while excluding LC3 from the parasitophorous vacuoles. These findings identify GP63 as a central effector that orchestrates host vesicular and apoptotic pathways to maintain parasitophorous vacuoles integrity and promote chronic infection, offering insights into potential therapeutic targets against Leishmaniasis.