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Researchers discovered that queuosine (Q), a chemical modification on specific tRNA molecules, plays a critical role in the ability of Leishmania mexicana parasites to cause disease. Q-tRNA levels increase dramatically when the parasite transitions from its insect vector to the mammalian host stage, and parasites lacking the enzyme needed for Q modification showed altered protein production patterns and reduced ability to survive in immune cells and cause infection in mice. This tRNA modification regulates gene expression through codon-biased translation, allowing the parasite to adapt to different host environments.
Why it matters
This finding reveals a previously unknown mechanism by which parasites control their virulence and adapt to different hosts, potentially offering new therapeutic targets for treating leishmaniasis. The research demonstrates that tRNA modifications represent an important regulatory layer in organisms lacking conventional transcriptional control, expanding our understanding of gene expression regulation beyond traditional mechanisms.
by Bankatesh Kumar, Julie Kovářová, Michala Boudová, Sneha Kulkarni, Thalia Pacheco Fernandez, Abhay Satoskar, Zdeněk Paris
The complex life cycle of the human parasite Leishmania mexicana requires rapid translational adaptation for survival in two distinct environments: the insect vector and the mammalian host. These protists lack conventional transcriptional control due to their unusual genome organization. Consequently, tRNA modifications may represent an additional mechanism for post-transcriptional regulation of gene expression. One such modification is queuosine (Q), which is incorporated at the anticodon wobble position 34 of specific tRNAs. Here, we demonstrate that Q-tRNA levels increase substantially during Leishmania differentiation from the insect stage to the mammalian-infective stage, implying an important role for virulence. Hence, we generated mutant cells lacking the enzyme responsible for Q incorporation, tRNA-guanine transglycosylase (TGT), which exhibited substantial changes in the proteome during differentiation in vitro. Specifically, downregulated proteins were enriched in NAU codons, whereas upregulated proteins predominantly contained NAC codons. Although LmxTGT knockout parasites exhibited normal growth and differentiation in vitro, they demonstrated impaired survival within macrophages and reduced pathogenicity in mice, highlighting the role of the Q-tRNAs under stress conditions. To our knowledge, we present here the first direct evidence that queuosine tRNA modification controls the infectivity of Leishmania via codon-biased translation. To date, gene expression regulation in Leishmania and other trypanosomatids has been attributed mostly to RNA stability and processing; however, our findings demonstrate that tRNA modifications also play a key regulatory role. Specifically, the Q-tRNA modification provides a novel layer of gene expression regulation, maintaining translational balance and supporting the parasite’s ability to adapt to changing environments, and contributing to Leishmania virulence.