The Tiny RNA That Reshapes a Parasite’s Protein Factory

The Leishmania parasite must survive in two very different environments: first inside a sand fly, and later inside the immune cells of a mammalian host. To make this transition, it needs to change which proteins it produces.

A new international study co-led by Prof. Shulamit Michaeli of Bar-Ilan University’s Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, who has recently won the Israel Prize, has uncovered a surprising mechanism behind this ability.

The researchers found that a tiny RNA molecule can help reshape the ribosome—the cellular machine that produces proteins—and influence which genetic instructions it translates.

More Than 100 Changes Inside the Ribosome

The team examined ribosomes from three Leishmania species during both major stages of the parasite’s life cycle.

They identified more than 100 chemical modifications on ribosomal RNA, the material forming the ribosome’s structural core. Most remained stable, but several changed as the parasite moved from the sand fly to the mammalian host.

One modification, known as Am479, consistently increased during the mammalian stage.

This modification is guided by a small nucleolar RNA, or snoRNA. Such molecules are normally known for directing chemical changes at precise locations on ribosomal RNA.

The new research shows that this snoRNA has another important role.

A Molecular Folding Assistant

The snoRNA also acts as a molecular chaperone, a folding assistant that helps ribosomal RNA form a particular three-dimensional structure.

When the researchers sharply reduced the amount of this snoRNA, the parasites grew more slowly and produced fewer proteins. They also found that active ribosomes completely lacking the Am479 modification were not formed, suggesting that it is essential for normal ribosome function.

Using high-resolution cryogenic electron microscopy, the researchers discovered that increasing the snoRNA changed the structure of a different ribosomal region called helix 68.

This region sits close to the route used by transfer RNA molecules during protein production.

When the researchers altered the snoRNA so it could no longer interact with helix 68, the ribosome largely returned to its original structure. Parasite growth improved, and many of the changes in protein production were reversed.

A Small Change With a Wide Impact

Increasing the snoRNA affected the translation of more than 1,000 messenger RNA molecules.

The altered ribosomes appeared to handle certain transfer RNAs and genetic “words,” known as codons, differently. This may allow the parasite to produce some proteins more efficiently than others as it adapts to a new host.

The findings challenge the traditional view of the ribosome as a fixed, passive machine. Instead, they show that its structure can be adjusted to fine-tune protein production.

Although the study does not yet offer a new treatment for leishmaniasis, it reveals a previously overlooked mechanism that may help parasites adapt and survive. Similar snoRNA interactions have also been observed in other organisms, including humans, suggesting that the discovery may have broader implications.

The study was co-led by Prof. Shulamit Michaeli of Bar-Ilan University, Prof. Ada Yonath of the Weizmann Institute of Science and Dr. K. Shanmugha Rajan, together with researchers from Bar-Ilan University, the Weizmann Institute, Duke University, Tokyo Metropolitan University, Institut Pasteur and the University of Würzburg. The research was accepted for publication in Nature Communications.