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Towards new antituberculotic targets: biochemical characterisation of mycobacterial RNase E/G

Agnes Csanadi^*,#, Mirijam-Elisabeth Zeller^*, Andras Miczak^#, Thierry Rose^¶, Thierry Bizebard and Vladimir R. Kaberdin^*

^* Max F. Perutz Laboratories, Dept of Microbiology and Immunobiology, University Departments at the Vienna Biocenter, Vienna, Austria, ^# Dept of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary, ^¶ Unité d'Immunogénétique Cellulaire, Institut Pasteur, Paris, France, Institut de Biologie Physico-chimique, Institut de Biologie Physico-chimique, Paris, France

CORRESPONDENCE: Agnes Csanadi, Dept of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary

The World Health Organization estimates that each year 3 million people die from tuberculosis (TB) and 8 million people become infected. No new anti-TB drugs have been introduced in the past 30 years, even though their development becomes increasingly important to face new challenges posed by multidrug-resistant and extensively drug-resistant strains and by acute infection with M. tuberculosis of HIV positive patients. Owing to its apparently important role in RNA metabolism, the RNase E/G family of endoribonucleases can be considered as a promising target for antimicrobial drugs. This consideration promted us to characterise biochemical properties of the M. tuberculosis RNase E/G homologue.

To learn more about specific properties of RNase E/G homologues a M. tuberculosis RNase E/G (MycRne) was overexpressed in E. coli and purified as a 6His-tagged polypeptide. To characterise MycRne, we used in vitro cleavage assays and primer extension analysis of total RNA extracted from mycobacteria.

We show that affinity purified MycRne has an endoribonucleolytic activity, which is dependent on the 5'-phosphorylation status of RNA. We could also show that RNase E/G has Mg²⁺ dependent activity and similar to E. coli RNase E, MycRne was able to cleave in an intercistronic region of the putative 9S precursor of 5S rRNA.

Although, similar to E. coli RNase E, the mycobacterial RNase E/G homologue plays a role in rRNA processing, the substrate specificities of these enzymes show differences. This suggests that RNase E/G can be used as a promising target for antimicrobial drugs that can be optimized to specifically target pathogenic species.