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

Aditya S. Paul, Alexandra Miliu, Joao A. Paulo, Jonathan M. Goldberg, Arianna M. Bonilla, Laurence Berry, Marie Seveno, Catherine Braun-Breton, Aziz L. Kosber, Brendan Elsworth, Jose S. N. Arriola, Maryse Lebrun, Steven P. Gygi, Mauld H. Lamarque () and Manoj T. Duraisingh ()
Additional contact information
Aditya S. Paul: Harvard T. H. Chan School of Public Health
Alexandra Miliu: Université de Montpellier
Joao A. Paulo: Harvard Medical School
Jonathan M. Goldberg: Harvard T. H. Chan School of Public Health
Arianna M. Bonilla: Harvard T. H. Chan School of Public Health
Laurence Berry: Université de Montpellier
Marie Seveno: Université de Montpellier
Catherine Braun-Breton: Université de Montpellier
Aziz L. Kosber: Harvard T. H. Chan School of Public Health
Brendan Elsworth: Harvard T. H. Chan School of Public Health
Jose S. N. Arriola: Harvard T. H. Chan School of Public Health
Maryse Lebrun: Université de Montpellier
Steven P. Gygi: Harvard Medical School
Mauld H. Lamarque: Université de Montpellier
Manoj T. Duraisingh: Harvard T. H. Chan School of Public Health

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Asexual proliferation of the Plasmodium parasites that cause malaria follows 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. By phosphoproteomic and chemical-genetic analysis, we isolate two functional targets of PfPP1 for egress: a HECT E3 protein-ubiquitin ligase; and GCα, a fusion protein composed of a guanylyl cyclase and a phospholipid transporter domain. We hypothesize that PfPP1 regulates lipid sensing by GCα and find that phosphatidylcholine stimulates PfPP1-dependent egress. PfPP1 acts as a key regulator that integrates multiple cell-intrinsic pathways with external signals to direct parasite egress from host cells.

Date: 2020
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DOI: 10.1038/s41467-020-17306-1

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