EhSSP2-mediated hijacking of the host APP/Aβ pathway drives biphasic apoptosis in Microsporidia infection

Microsporidia are obligate intracellular parasites that pose a significant threat to both immunocompetent and immunocompromised individuals, with current therapies lacking effectiveness against crucial lifecycle stages. In this study, we identify a novel sporoplasm surface protein, EhSSP2, from Encephalitozoon hellem, which directly interacts with the host amyloid precursor protein (APP) through conserved GXXXG motifs, specifically targeting APP's amyloid-β (Aβ) domain. This interaction establishes a functional SSP2-APP-VDAC1-SSP1 signaling axis, whereby EhSSP2 enhances BACE1 expression, promoting APP cleavage and subsequent Aβ production, thereby linking to mitochondrial VDAC1. Importantly, E. hellem exhibits biphasic regulation of apoptosis. Early suppression of apoptosis occurs to facilitate intracellular replication, followed by activation during later stages to induce mitochondrial dysfunction and promote spore dissemination. Pharmacological validation confirms that apoptosis is essential for efficient spore release. Our findings reveal a novel strategy by which microsporidia hijack the host APP/Aβ pathway for their propagation, providing mechanistic insights into organelle hijacking and potential therapeutic targets for microsporidiosis.