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

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, William J. Sullivan, Seán E. O’Leary and Vern B. Carruthers ()
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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
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
Wenzhao Dong: University of Michigan
Jailson Brito Querido: University of Michigan
William J. Sullivan: Indiana University School of Medicine
Seán E. O’Leary: University of California Riverside
Vern B. Carruthers: University of Michigan Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48685-4

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