Divergent Autophagy Pathways in Plasmodium: Mechanisms, Functions, and Therapeutic Potential.

Autophagy is a highly conserved degradative and recycling pathway essential for maintaining cellular homeostasis. Although its molecular machinery is well characterized in yeast and mammalian systems, it is less studied in the early-diverging apicomplexan parasite Plasmodium, the causative agent of malaria. Plasmodium possesses a reduced yet functional repertoire of autophagy-related (ATG) proteins, suggesting adaptations of this pathway to parasite-specific biology. Among these, ATG8, a ubiquitin-like protein, has emerged as a central marker and key effector of plasmodial autophagy. Its branched localization and association with the relict plastid (apicoplast) membrane indicate roles beyond canonical degradative autophagy, particularly in organelle maintenance and biogenesis. ATG7, an essential E1-like enzyme, activates ATG8 and facilitates its lipidation, thereby regulating organelle turnover and development. This process is further supported by a conserved conjugation system involving ATG3 (E2-like enzyme) and the ATG12, ATG5, ATG16 complex, functioning as a ligase to enable ATG8 membrane association. ATG4, a cysteine protease, is critical for recycling lipidated ATG8 and maintaining its cytosolic pool, while the homolog Otu can partially compensate for its function. ATG18 also plays an important role in apicoplast biogenesis and maintenance. Collectively, these findings highlight both canonical and non-canonical roles of autophagy proteins in Plasmodium, driving metabolic reprogramming, intracellular remodeling, and stage-specific differentiation, and support their potential as targets for new antimalarial therapies.