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Phosphorylation of Rhoptry Protein Rhoph3 Is Critical for Host Cell Invasion by the Malaria Parasite

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Phosphorylation of Rhoptry Protein Rhoph3 Is Critical for Host Cell Invasion by the Malaria Parasite RESEARCH ARTICLE Molecular Biology and Physiology crossm Downloaded from Phosphorylation of Rhoptry Protein RhopH3 Is Critical for Host Cell Invasion by the Malaria Parasite Roseleen Ekka,a Ankit Gupta,a* Sonika Bhatnagar,a Pawan Malhotra,b Pushkar Sharmaa http://mbio.asm.org/ aEukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India bInternational Center for Genetic Engineering and Biotechnology, New Delhi, India Roseleen Ekka and Ankit Gupta contributed equally to this work; the order of authors was decided on the basis of the alphabetical order of the surnames and the time spent in the laboratory. ABSTRACT Merozoites formed after asexual division of the malaria parasite invade the host red blood cells (RBCs), which is critical for initiating malaria infection. The process of invasion involves specialized organelles like micronemes and rhoptries on October 21, 2020 at NATIONAL INSTITUTE OF IMMUNOLOGY (NII) that discharge key proteins involved in interaction with host RBC receptors. RhopH complex comprises at least three proteins, which include RhopH3. RhopH3 is critical for the process of red blood cell (RBC) invasion as well as intraerythrocytic develop- ment of human malaria parasite Plasmodium falciparum. It is phosphorylated at ser- ine 804 (S804) in the parasite; however, it is unclear if phosphorylation regulates its function. To address this, a CRISPR-CAS9-based approach was used to mutate S804 to alanine (A) in P. falciparum. Using this phosphomutant (R3_S804A) of RhopH3, we demonstrate that the phosphorylation of S804 is critical for host RBC invasion by the parasite but not for its intraerythrocytic development. Importantly, the phosphoryla- tion of RhopH3 regulates its localization to the rhoptries and discharge from the parasite, which is critical for RBC invasion. We also identified P. falciparum CDPK1 (PfCDPK1) as a possible candidate kinase for RhopH3-S804 phosphorylation and found that it regulates RhopH3 secretion from the parasite. These findings provide novel insights into the role of phosphorylation in rhoptry release and invasion, which is poorly understood. IMPORTANCE Host cell invasion by the malaria parasite is critical for establishing in- fection in human host and is dependent on discharge of key ligands from organelles like rhoptry and microneme, and these ligands interact with host RBC receptors. In the present study, we demonstrate that phosphorylation of a key rhoptry protein, Citation Ekka R, Gupta A, Bhatnagar S, RhopH3, is critical for host invasion. Phosphorylation regulates its localization to Malhotra P, Sharma P. 2020. Phosphorylation of rhoptries and discharge from the parasite. rhoptry protein RhopH3 is critical for host cell invasion by the malaria parasite. mBio KEYWORDS phosphorylation, malaria, signaling, invasion, host cell invasion, protein 11:e00166-20. https://doi.org/10.1128/mBio phosphorylation .00166-20. Editor Louis M. Weiss, Albert Einstein College of Medicine lasmodium, the causative pathogen for malaria, claims more than 400,000 lives Copyright © 2020 Ekka et al. This is an open- access article distributed under the terms of Pevery year (1). Plasmodium falciparum is responsible for most of the reported the Creative Commons Attribution 4.0 mortality caused by malaria. It is the asexual development in human erythrocytes which International license. is mainly responsible for pathogenesis of the disease. After the mosquito bite and Address correspondence to Pushkar Sharma, release of sporozoites, the parasite develops inside the hepatocytes, resulting in [email protected]. * Present address: Ankit Gupta, Department of generation of thousands of merozoites. After release into the bloodstream, merozoites Biochemistry, All India Institute of Medical invade red blood cells (RBCs) followed by intraerythrocytic development from ring- Sciences (AIIMS), Munshiganj, Raebareli, U.P., shaped forms to trophozoites followed by asexual division resulting in ϳ30 merozoites India. per schizont, which egress from the infected RBC (iRBC) to reinvade fresh RBCs. Received 23 January 2020 Accepted 9 September 2020 The process of invasion is a well-orchestrated series of events, which involves Published 6 October 2020 merozoite attachment, rearrangement of host RBC membrane, reorientation of the ® September/October 2020 Volume 11 Issue 5 e00166-20 mbio.asm.org 1.
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