EnP1 exploits H2Aub-dependent epigenetic reprogramming to promote microsporidia proliferation in host cells.

Microsporidia, as opportunistic parasitic pathogens, constitute a formidable threat to human health. Although the regulatory circuitry of the nucleus-targeted effector EnP1 remains highly intricate and only partially characterized, our study identifies histone H2A as a novel binding partner of EnP1. Furthermore, we demonstrate that both EnP1 overexpression and microsporidia infection induce monoubiquitination of H2A (H2Aub) through downregulation of BAP1 expression. Subsequent mechanistic analyses revealed that elevated H2Aub levels positively correlate with enhanced microsporidian proliferation, whereas attenuation of H2Aub markedly suppresses pathogen expansion. Furthermore, EnP1 orchestrates the enrichment of H2Aub at the SLC7A11 promoter, driving its transcriptional upregulation. Collectively, these findings underscore that EnP1 modulates the ferroptosis state of host cells through H2Aub-mediated epigenetic reprogramming, ultimately facilitating pathogen propagation. This study endeavors to elucidate the critical survival strategies of microsporidia within host cells mediated by EnP1 and to unravel the multifaceted interplay between these pathogens and their hosts.