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

PLoS Pathog. 2018 Aug 22;14(8):e1007249. doi: 10.1371/journal.ppat.1007249. eCollection 2018 Aug.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anopheles / parasitology*
  • Cytoplasmic Granules / metabolism
  • Female
  • Humans
  • Life Cycle Stages / genetics
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / transmission*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Organisms, Genetically Modified
  • Phosphate-Binding Proteins
  • Plasmodium falciparum* / genetics
  • Plasmodium falciparum* / growth & development
  • Plasmodium falciparum* / metabolism
  • Protein Biosynthesis* / genetics
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • Protozoan Proteins / metabolism
  • Protozoan Proteins / physiology
  • Sequence Homology
  • Stress, Physiological

Substances

  • LANCL2 protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphate-Binding Proteins
  • Protozoan Proteins

Grant support

The work was funded by the Deutsche Forschungsgemeinschaft (to GP, grant-numbers: PR905/3-2, PR905/4-1; PR905/7-1; PR905/8-2). CJN received a Theodore von Kármán fellowship from the RWTH Aachen University. GP is recipient of a Heisenberg professorship of the Deutsche Forschungsgemeinschaft. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.