Malaria parasite evades mosquito immunity by glutaminyl cyclase-mediated posttranslational protein modification

Proc Natl Acad Sci U S A. 2022 Aug 30;119(35):e2209729119. doi: 10.1073/pnas.2209729119. Epub 2022 Aug 22.

Abstract

Glutaminyl cyclase (QC) modifies N-terminal glutamine or glutamic acid residues of target proteins into cyclic pyroglutamic acid (pGlu). Here, we report the biochemical and functional analysis of Plasmodium QC. We show that sporozoites of QC-null mutants of rodent and human malaria parasites are recognized by the mosquito immune system and melanized when they reach the hemocoel. Detailed analyses of rodent malaria QC-null mutants showed that sporozoite numbers in salivary glands are reduced in mosquitoes infected with QC-null or QC catalytically dead mutants. This phenotype can be rescued by genetic complementation or by disrupting mosquito melanization or phagocytosis by hemocytes. Mutation of a single QC-target glutamine of the major sporozoite surface protein (circumsporozoite protein; CSP) of the rodent parasite Plasmodium berghei also results in melanization of sporozoites. These findings indicate that QC-mediated posttranslational modification of surface proteins underlies evasion of killing of sporozoites by the mosquito immune system.

Keywords: glutaminyl cyclase; immune evasion; melanization; pyroglutamic acid; sporozoite.

MeSH terms

  • Aminoacyltransferases* / immunology
  • Animals
  • Culicidae* / immunology
  • Glutamic Acid / metabolism
  • Glutamine / metabolism
  • Humans
  • Malaria* / genetics
  • Malaria* / immunology
  • Malaria* / parasitology
  • Plasmodium berghei / genetics
  • Plasmodium berghei / immunology
  • Protein Processing, Post-Translational* / immunology
  • Protozoan Proteins / immunology
  • Sporozoites* / immunology

Substances

  • Protozoan Proteins
  • Glutamine
  • Glutamic Acid
  • Aminoacyltransferases
  • glutaminyl-peptide cyclotransferase