Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes

Abstract

Asexual proliferation of the Plasmodium parasites that cause malaria follow a developmental program that alternates non-canonical intraerythrocytic replication with dissemination to new host cells. We carried out a functional analysis of the Plasmodium falciparum homolog of Protein Phosphatase 1 (PfPP1), a universally conserved cell cycle factor in eukaryotes, to investigate regulation of parasite proliferation. PfPP1 is indeed required for efficient replication, but is absolutely essential for egress of parasites from host red blood cells. A phosphoproteomic screen and chemical-genetic analysis provided evidence for a HECT E3 protein-ubiquitin ligase, as well as a fusion protein with guanylyl cyclase and phospholipid transporter domains, as functional targets of PfPP1. Extracellular phosphatidylcholine stimulates PfPP1-dependent egress. Parasite PfPP1 acts as a master regulator that can integrate multiple cell-intrinsic pathways with external signals to direct parasite egress from host cells.