Plasmodium falciparum S-Adenosylmethionine Synthetase Is Essential for Parasite Survival through a Complex Interaction Network with Cytoplasmic and Nuclear Proteins

Microorganisms, vol. 10, pp. 1419

Abstract

S-adenosylmethionine synthetase (SAMS) is a key enzyme for the synthesis of the lone methyl donor S-adenosyl methionine (SAM), which is involved in transmethylation reactions and hence required for cellular processes such as DNA, RNA, and histone methylation, but also polyamine biosynthesis and proteostasis. In the human malaria parasite Plasmodium falciparum, PfSAMS is encoded by a single gene and has been suggested to be crucial for malaria pathogenesis and transmission; however, to date, PfSAMS has not been fully characterized. To gain deeper insight into the function of PfSAMS, we generated a conditional gene knockdown (KD) using the glmS ribozyme system. We show that PfSAMS localizes to the cytoplasm and the nucleus of blood-stage parasites. PfSAMS-KD results in reduced histone methylation and leads to impaired intraerythrocytic growth and gametocyte development. To further determine the interaction network of PfSAMS, we performed a proximity-dependent biotin identification analysis. We identified a complex network of 1114 proteins involved in biological processes such as cell cycle control and DNA replication, or transcription, but also in phosphatidylcholine and polyamine biosynthesis and proteasome regulation. Our findings highlight the diverse roles of PfSAMS during intraerythrocytic growth and sexual stage development and emphasize that PfSAMS is a potential drug target.

Authors 12

1. Jean Pierre Musabyimana Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

2. Ute Distler

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Proteomics Core Facility, Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany

3. Juliane Sassmannshausen Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

4. Christina Berks Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

5. Janice Manti Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

6. Sandra Bennink Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

7. Lea Blaschke Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

8. Paul‐Christian Burda

   Deutsches Elektronen-Synchrotron DESY · Universität Hamburg · Centre for Structural Systems Biology

   Affiliation as printed

   Centre for Structural Systems Biology (CSSB) c/o DESY, Bernhard Nocht Institute, University of Hamburg, Notkestraße 85, Building 15, 22607 Hamburg, Germany

9. Ansgar Flammersfeld Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

10. Stefan Tenzer

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Proteomics Core Facility, Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany

11. Che Julius Ngwa Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

    RWTH Aachen University

    Affiliation as printed

    Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

12. Gabriele Pradel corresponding Aachen Institute of Zoology (Biology 2) Division of Cellular and Applied Infection Biology

    RWTH Aachen University

    Affiliation as printed

    Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany