Queuine Is a Nutritional Regulator of Entamoeba histolytica Response to Oxidative Stress and a Virulence Attenuator

Shruti Nagaraja (1) , Maggi W Cai (2, 3) , Jingjing Sun (4) , Hugo Varet (5, 6) , Lotem Sarid (1) , Meirav Trebicz-Geffen (1) , Yana Shaulov (1) , Mohit Mazumdar (7) , Rachel Legendre (5, 6) , Jean-Yves Coppée (5, 6) , Thomas J Begley (5) , Peter C Dedon (3, 4) , Samudrala Gourinath (7) , Nancy Guillen (8) , Yumiko Saito-Nakano (9) , Chikako Shimokawa (9) , Hajime Hisaeda (9) , Serge Ankri (1)

1 Technion - Israel Institute of Technology [Haifa]
2 NUS - National University of Singapore
3 SMART - Singapore-MIT Alliance for Research and Technology
4 MIT - Massachusetts Institute of Technology
5 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
6 C2RT - Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research
7 JNU - Jawaharlal Nehru University
8 Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions
9 National Institute of Infectious Diseases, Shinjuku-ku

Queuosine is a naturally occurring modified ribonucleoside found in the first position of the anticodon of the transfer RNAs for Asp, Asn, His, and Tyr. Eukaryotes lack pathways to synthesize queuine, the nucleobase precursor to queuosine, and must obtain it from diet or gut microbiota. Here, we describe the effects of queuine on the physiology of the eukaryotic parasite Entamoeba histolytica, the causative agent of amebic dysentery. Queuine is efficiently incorporated into E. histolytica tRNAs by a tRNA-guanine transglycosylase (EhTGT) and this incorporation stimulates the methylation of C38 in tRNAAspGUC. Queuine protects the parasite against oxidative stress (OS) and antagonizes the negative effect that oxidation has on translation by inducing the expression of genes involved in the OS response, such as heat shock protein 70 (Hsp70), antioxidant enzymes, and enzymes involved in DNA repair. On the other hand, queuine impairs E. histolytica virulence by downregulating the expression of genes previously associated with virulence, including cysteine proteases, cytoskeletal proteins, and small GTPases. Silencing of EhTGT prevents incorporation of queuine into tRNAs and strongly impairs methylation of C38 in tRNAAspGUC, parasite growth, resistance to OS, and cytopathic activity. Overall, our data reveal that queuine plays a dual role in promoting OS resistance and reducing parasite virulence.

Mots clés: Entamoeba histolytica; oxidative stress; tRNA modification; virulence

Domaines: Sciences du Vivant [q-bio]

Shruti Nagaraja, Maggi W Cai, Jingjing Sun, Hugo Varet, Lotem Sarid, et al.. Queuine Is a Nutritional Regulator of Entamoeba histolytica Response to Oxidative Stress and a Virulence Attenuator. mBio, 2021, 12 (2), pp.e03549-20. ⟨10.1128/mBio.03549-20⟩. ⟨pasteur-03165902⟩