A multifaceted model of Entamoeba histolytica KERP2 regulating gene expression and host cell responses.

Entamoeba histolytica causes amoebiasis and damages intestinal epithelium, but how individual parasite factors coordinate parasite gene regulation with host remodeling is unclear. We investigate lysine- and glutamic acid-rich protein 2, a factor linked to the host brush border. Sequence analysis, imaging, and functional assays show that lysine- and glutamic acid-rich protein 2 accumulates in the parasite nucleus, binds AT-rich DNA, and modulates transcriptional programs related to Amoebiasis, including cysteine protease and sulfur metabolism. During parasite-epithelium contact, the protein enters host epithelial cells and is associated with increased deoxyribonucleic acid synthesis, altered cytoskeletal regulators, actin remodeling, and reduced barrier integrity. Here, we propose a working model in which lysine- and glutamic acid-rich protein 2 links parasite chromatin-associated regulation with host epithelial remodeling during contact. Notably, our data support host cytoskeletal and junctional phenotypes and do not yet establish a direct role for it in host chromatin regulation. Together, these observations suggest a potentially broader mechanism by which extracellular pathogens deploy effectors to optimize virulence and adapt to diverse host environments.