Abstract

Microsporidia are known intracellular pathogens that infect nearly all animals and deeply manipulate host mitochondrial homeostasis for survival. Here, we report a novel mechanism by which the human-pathogenic Encephalitozoon hellem modulates the mitophagy machinery of its host. We identified the secreted protein EhPTP4 as a key effector in disrupting selective degradation processes in the infected cells. EhPTP4 is found to localize within the nucleus of infected cells, where it induces increased expression of endoplasmic reticulum-associated degradation (ERAD) pathway components, including HSPA5, HERPUD1, and PDIA4. This induction enhances protein ubiquitination in host cells and leads to the degradation of BNIP3L, a critical regulator of mitophagy. Investigation into the molecular interaction network revealed that EhPTP4 interacts with host corepressor RCOR1 and histone H3. This interaction modulates histone acetylation, specifically at H3K14ac sites, thereby further influencing the expression of a key ERAD gene, HERPUD1. This study uncovers a sophisticated strategy by which microsporidia manipulates both ER stress response and the histone acetylation to suppress mitophagy. These findings provide new insights into the mechanisms of microsporidian pathogenesis. Microsporidian parasites, known for their intricate manipulation of host cellular processes, have been found to employ novel mechanisms in disrupting mitochondrial homeostasis. This study investigates Encephalitozoon hellem , a human-pathogenic microsporidian, and its strategy to inhibit mitophagy, the cellular process responsible for degrading damaged mitochondria. The research reveals that E. hellem secretes a key effector protein, EhPTP4, which localizes within the nucleus of host cells. This protein enhances the expression of components related to the Endoplasmic Reticulum-Associated Degradation (ER