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Translation initiation factor eIF1.2 promotes Toxoplasma stage conversion by regulating levels of key differentiation factors

Author

Listed:
  • Fengrong Wang

    (University of Michigan Medical School)

  • Michael J. Holmes

    (Indiana University School of Medicine)

  • Hea Jin Hong

    (University of California Riverside)

  • Pariyamon Thaprawat

    (University of Michigan Medical School
    University of Michigan Medical School)

  • Geetha Kannan

    (University of Michigan Medical School)

  • My-Hang Huynh

    (University of Michigan Medical School)

  • Tracey L. Schultz

    (University of Michigan Medical School)

  • M. Haley Licon

    (Whitehead Institute)

  • Sebastian Lourido

    (Whitehead Institute
    Massachusetts Institute of Technology)

  • Wenzhao Dong

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Jailson Brito Querido

    (University of Michigan
    University of Michigan
    University of Michigan)

  • William J. Sullivan

    (Indiana University School of Medicine
    Indiana University School of Medicine)

  • Seán E. O’Leary

    (University of California Riverside
    University of California Riverside)

  • Vern B. Carruthers

    (University of Michigan Medical School)

Abstract

The parasite Toxoplasma gondii persists in its hosts by converting from replicating tachyzoites to latent bradyzoites housed in tissue cysts. The molecular mechanisms that mediate T. gondii differentiation remain poorly understood. Through a mutagenesis screen, we identified translation initiation factor eIF1.2 as a critical factor for T. gondii differentiation. A F97L mutation in eIF1.2 or the genetic ablation of eIF1.2 (∆eif1.2) markedly impeded bradyzoite cyst formation in vitro and in vivo. We demonstrated, at single-molecule level, that the eIF1.2 F97L mutation impacts the scanning process of the ribosome preinitiation complex on a model mRNA. RNA sequencing and ribosome profiling experiments unveiled that ∆eif1.2 parasites are defective in upregulating bradyzoite induction factors BFD1 and BFD2 during stress-induced differentiation. Forced expression of BFD1 or BFD2 significantly restored differentiation in ∆eif1.2 parasites. Together, our findings suggest that eIF1.2 functions by regulating the translation of key differentiation factors necessary to establish chronic toxoplasmosis.

Suggested Citation

  • Fengrong Wang & Michael J. Holmes & Hea Jin Hong & Pariyamon Thaprawat & Geetha Kannan & My-Hang Huynh & Tracey L. Schultz & M. Haley Licon & Sebastian Lourido & Wenzhao Dong & Jailson Brito Querido &, 2024. "Translation initiation factor eIF1.2 promotes Toxoplasma stage conversion by regulating levels of key differentiation factors," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48685-4
    DOI: 10.1038/s41467-024-48685-4
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    References listed on IDEAS

    as
    1. Sarah L. Sokol-Borrelli & Sarah M. Reilly & Michael J. Holmes & Stephanie B. Orchanian & Mackenzie D. Massmann & Katherine G. Sharp & Leah F. Cabo & Hisham S. Alrubaye & Bruno Martorelli Di Genova & M, 2023. "A transcriptional network required for bradyzoite development in Toxoplasma gondii is dispensable for recrudescent disease," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Matteo Lunghi & Joachim Kloehn & Aarti Krishnan & Emmanuel Varesio & Oscar Vadas & Dominique Soldati-Favre, 2022. "Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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