Characterization of an atypical eIF4E ortholog in Leishmania, leishIF4E-6

Nitin Tupperwar, Rohit Shrivastava, Nofar Baron, Orli Korchev, Irit Dahan, Michal Shapira

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Leishmania parasites are digenetic protists that shuffle between sand fly vectors and mammalian hosts, transforming from flagellated extracellular promastigotes that reside within the intestinal tract of female sand flies to the obligatory intracellular and non-motile amastigotes within mammalian macrophages. Stage differentiation is regulated mainly by post-transcriptional mecha-nisms, including translation regulation. Leishmania parasites encode six different cap-binding pro-teins, LeishIF4E1-6, that show poor conservation with their counterparts from higher eukaryotes and among themselves. In view of the changing host milieu encountered throughout their life cycle, we propose that each LeishIF4E has a unique role, although these functions may be difficult to de-termine. Here we characterize LeishIF4E-6, a unique eIF4E ortholog that does not readily associate with m7 GTP cap in either of the tested life forms of the parasite. We discuss the potential effect of substituting two essential tryptophan residues in the cap-binding pocket, expected to be involved in the cap-binding activity, as judged from structural studies in the mammalian eIF4E. LeishIF4E-6 binds to LeishIF4G-5, one of the five eIF4G candidates in Leishmania. However, despite this binding, LeishIF4E-6 does not appear to function as a translation factor. Its episomal overexpression causes a general reduction in the global activity of protein synthesis, which was not observed in the hemi-zygous deletion mutant generated by CRISPR-Cas9. This genetic profile suggests that LeishIF4E-6 has a repressive role. The interactome of LeishIF4E-6 highlights proteins involved in RNA metabolism such as the P-body marker DHH1, PUF1 and an mRNA-decapping enzyme that is homologous to the TbALPH1.

Original languageEnglish
Article number12720
JournalInternational Journal of Molecular Sciences
Volume22
Issue number23
DOIs
StatePublished - 1 Dec 2021

Keywords

  • LeishIF4E-6
  • LeishIF4G
  • Leishmania
  • Protein synthesis
  • Translation regulation

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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