Trypanosomes use a zinc-finger nuclease to balance zinc supply

A collaborative team from the Faculty of Life Sciences in Dundee and the University of Porto has discovered a trypanosome protein that controls zinc transporter expression in response to environmental zinc; the findings are described in a paper published in Nucleic Acids Research.

We all need vitamins, minerals and nutrients to survive and so do parasites, including trypanosomatid parasites such as Trypanosoma brucei, Trypanosoma cruzi and Leishmania, which cause devastating and lethal Neglected Tropical Diseases. To access these essential supplies, cell-surface protein channels selectively transport specific metals, nucleotides, sugars, amino acids and lipids.

Because the availability of essential nutrients varies substantially in the insects that transmit these parasites and in human host tissues, supply must be regulated. By exploring the response to zinc, the team hoped to identify both a specific regulatory protein and the regulatory sequences within messenger RNA; gene expression regulation operates almost exclusively post-transcription in trypanosomatids, via RNA untranslated sequences.

David Horn, Professor of Parasite Molecular Biology, said, “Professor Ana Tomás and I discussed the idea of using genome-wide screening in T. brucei to identify a mysterious zinc transport regulator when I visited Porto some years ago. It really was one of those special moments in the lab when Teresa and Anna ultimately identified the top hit, a protein that contained both a probable zinc-sensor RNA-binding module and an effector nuclease module, connected by a flexible linker. This immediately suggested an elegant mechanism for zinc-dependent control of zinc transport”.

Teresa Leão, the first author on the paper said, “My PhD project was primarily focussed on zinc uptake in Leishmania parasites, and our hypothesis was that a zinc transport regulator would be similar in Leishmania and in T. brucei. So it was a great outcome when we found a conserved, nuclear-localised protein with a string of zinc-finger type motifs known as zinc knuckles, hence the new name, Zinc Nuclear Knuckles 1 (ZNK1). It was even better when follow-up experiments showed that ZNK1 is specifically required to control zinc transporter expression and zinc accumulation”.

Anna Trenaman, a post-doc who assisted Teresa and supervised the work in Dundee said, “We saw a clear signature of zinc transporter negative control in prior Massive Parallel Reporter Assays, so this was a great opportunity to further exploit our powerful screening platforms to identify the zinc regulator”.

Gustavo Bravo Ruiz, another post-doc in Dundee and co-author working with multiple RNA-binding proteins said, “We’re hoping to understand the RNA cis-regulatory code in trypanosomatids and are already predicting gene expression controls using RNA untranslated sequences alone. The discovery of ZNK1 presented another opportunity and we identified a motif in the zinc transporter untranslated sequences that is indeed predictive of experimentally measured ZNK1-based negative control”.

David concluded, “Despite their importance, there are very few clearly elucidated pathways linking extrinsic signals to gene expression changes in trypanosomatids. Our findings now present a clear example of metal-ion-responsive regulation by an RNA-binding protein”.

The researchers now hope to discover additional conserved ‘first-responder’ RNA-binding proteins in trypanosomatids, further revealing how these deadly parasites adapt to their host environments. 

See the paper here: Zinc-dependent turnover of ZIP3 transporter mRNA by trypanosome ZNK1

The work was supported by Wellcome.