Plasmodium falciparum ring‐infected erythrocyte surface antigen 3 ( PfRESA3 ) is a cytoskeleton‐interacting protein and potential co‐chaperone

Plasmodium falciparum exports proteins into host erythrocytes for survival, but the roles of many of these proteins remain unexplored. Here, we used recombinant protein constructs and antibodies corresponding to Plasmodium falciparum ring‐infected erythrocyte surface antigen‐3 (PfRESA3) to identify it as a dense granule merozoite protein exported early to the inner erythrocyte membrane, where it associates with the cytoskeleton. Constructs lacking the J domain bound inside‐out vesicles, implicating PRESAN and DnaJ‐X in cytoskeletal interactions. Recombinant PfRESA3 constructs stimulated the ATPase activity of human HsHSPA8 and enhanced malate dehydrogenase (MDH) refolding. However, truncated PfRESA3 constructs did not significantly enhance MDH refolding by HsHSPA8. These findings suggest PfRESA3 modulates host HsHSPA8 to support cytoskeletal remodeling/parasite protein folding early in infection. Impact statement Our study uncovers a high‐stakes hijacking of the human erythrocyte by Plasmodium falciparum. By identifying PfRESA3 as a potential co‐chaperone that anchors to the host's cytoskeleton and recruits human chaperones, this study reveals a sophisticated survival strategy. It exposes a critical vulnerability in the parasite's early development inside the human erythrocyte.