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July 17th, 2025
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Ben-Gurion University of the Negev
microbiology
biorxiv

Beyond translation initiation: dual regulatory interactions with phosphorylated and non-phosphorylated LeishIF4E1

Pullaihagari, D.Open in Google Scholar•Baron, N.Open in Google Scholar•Purushostam, R.Open in Google Scholar•Kamus-Elimeleh, D.Open in Google Scholar•Dror, S.Open in Google Scholar•Levin, L.Open in Google Scholar•Shapira, M.Open in Google Scholar

Translation initiation in eukaryotes begins with the assembly of the cap-binding eIF4F complex at the 5 ends of mRNAs, through eIF4E. Among the six orthologs of eIF4E in Leishmania, LeishIF4E1 is intriguing, as it does not bind any Leishmania eIF4G. It is expressed in both life-forms, maintaining efficient cap-binding activity for translation initiation, unlike other LeishIF4Es. We identified two novel phosphorylation sites specifically S108, and S112, along with S203, which is conserved with the mammalian phosphorylation site. A non-phosphorylatable, tagged, mutant of LeishIF4E1 created by substituting the phosphorylated serine residues with alanine [S(108,112,203)A] was generated. The phosphorylation status did not affect the binding of LeishIF4E1 to translation initiation factors. However, the phosphorylated LeishIF4E1 interacted with proteins involved in DNA and chromatin structure, while non-phosphorylated LeishIF4E1 interacted with proteins that assist cells under stress and unfavorable conditions, particularly in gluconeogenesis. This indicates that LeishIF4E1 may play secondary regulatory roles. RNA sequencing of transcripts associated with LeishIF4E1 showed a tenfold decrease in binding to the non-phosphorylated form, highlighting the significance of its phosphorylation in transcript interaction. GO enrichment analysis indicated distinct phosphorylation-dependent transcript specificities for each form. This study highlights the critical role of LeishIF4E1 phosphorylation in modulating the selectivity of protein interactome and transcript associations, extending the role of LeishIF4E1 beyond its well-established function in translation initiation.

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