Research Article: A seven-helix protein constitutes stress granules crucial for regulating translation during human-to-mosquito transmission of Plasmodium falciparum

Date Published: August 22, 2018

Publisher: Public Library of Science

Author(s): Sandra Bennink, Andreas von Bohl, Che J. Ngwa, Leonie Henschel, Andrea Kuehn, Nicole Pilch, Tim Weißbach, Alina N. Rosinski, Matthias Scheuermayer, Urska Repnik, Jude M. Przyborski, Allen M. Minns, Lindsey M. Orchard, Gareth Griffiths, Scott E. Lindner, Manuel Llinás, Gabriele Pradel, Kirk W. Deitsch.


The complex life-cycle of the human malaria parasite Plasmodium falciparum requires a high degree of tight coordination allowing the parasite to adapt to changing environments. One of the major challenges for the parasite is the human-to-mosquito transmission, which starts with the differentiation of blood stage parasites into the transmissible gametocytes, followed by the rapid conversion of the gametocytes into gametes, once they are taken up by the blood-feeding Anopheles vector. In order to pre-adapt to this change of host, the gametocytes store transcripts in stress granules that encode proteins needed for parasite development in the mosquito. Here we report on a novel stress granule component, the seven-helix protein 7-Helix-1. The protein, a homolog of the human stress response regulator LanC-like 2, accumulates in stress granules of female gametocytes and interacts with ribonucleoproteins, such as CITH, DOZI, and PABP1. Malaria parasites lacking 7-Helix-1 are significantly impaired in female gametogenesis and thus transmission to the mosquito. Lack of 7-Helix-1 further leads to a deregulation of components required for protein synthesis. Consistently, inhibitors of translation could mimic the 7-Helix-1 loss-of-function phenotype. 7-Helix-1 forms a complex with the RNA-binding protein Puf2, a translational regulator of the female-specific antigen Pfs25, as well as with pfs25-coding mRNA. In accord, gametocytes deficient of 7-Helix-1 exhibit impaired Pfs25 synthesis. Our data demonstrate that 7-Helix-1 constitutes stress granules crucial for regulating the synthesis of proteins needed for life-cycle progression of Plasmodium in the mosquito vector.

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In eukaryotes, proteins comprising seven helix domains are classified as receptors capable of binding a high variety of ligands. Because many of these receptors transduce signals to heterotrimeric G proteins, they are commonly referred to as G protein-coupled receptors (GPCR) (reviewed in [1]). Alternative names include serpentine receptors (SRs), seven-transmembrane receptors or seven-helix proteins. These proteins are usually integral parts of cell membranes and able to perceive a broad spectrum of stimuli, such as peptides, small molecules or light (reviewed in [1]). Recent studies have further reported on GPCR-like molecules that are not integrated in cell membranes but found in the cytoplasm of a variety of mammalian tissues, such as liver, brain or muscle cells. Due to their homologies with prokaryotic lanthionine cyclases (LanC) of gram-positive bacteria, these GPCR-like proteins were termed LanC-like (LanCL) proteins [2–5].

The human-to-mosquito transmission of P. falciparum requires a high degree of tight coordination allowing the parasite to rapidly adapt to the changing environment. The parasite prepares for transmission by the formation of intraerythrocytic gametocytes, which immediately convert into male and female gametes, once taken up by the blood-feeding mosquito. In order to pre-adapt to the change of host, female gametocytes store several hundred mRNAs in specific SGs via translational repressors like DOZI, CITH or Puf2. These repressed mRNAs code for proteins required for further development in the mosquito, particularly the ookinete and oocyst stages ([14–16]; reviewed in [12]). With the onset of gametogenesis, the repressed mRNAs become accessible again for ribosomes, hence female gametogenesis requires a rapid increase in translational activities to ensure parasite survival. Despite the crucial function of the gametocyte-specific SGs for parasite transmission and thus spread of the tropical disease, to date not much is known about their compositions and the molecules involved in the translational fine control.