Functional divergence of SIR2 orthologs between trypanosomatid parasites

• Leishmania parasites lack nuclear SIR2 enzymes.
• LiSIR2rp3 is dispensable while LiSIR2rp2 could not be deleted.
• Multiple extrachromosomal amplicons bearing the LiSIR2rp2 gene are naturally present in WT strains.
• LiSIR2rp2 interferes with parasite proliferation in relation to NAD+ availability.

SIR2 proteins are NAD+-dependent deacetylases involved in epigenetic control of gene expression and metabolic regulation through post-translational modification of diverse target proteins. In pathogens, these enzymes are considered as attractive drug targets involved in key aspects of the infectious cycle. Leishmania infantum LiSIR2rp1 was among the first non-nuclear and essential SIR2 deacetylases described in eukaryotes. Here, we show that the two other LiSIR2rp2 and LiSIRrp3 paralogs are both located in mitochondria. Gene deletion experiments show that LiSIR2rp3 is not required for parasite survival. Surprisingly, multiple extrachromosomal amplicons bearing the LiSIR2rp2 gene are constitutively produced in wild type strains. Consequently, a knockout of this gene could not be obtained, even after episomal rescue experiments. We further provide genetic and biochemical evidence showing that SIR2rp2 protein directly affects parasite proliferation in relation to NAD+ bioavailability. Together, these results highlight unexpected genus-specific divergence of the SIR2 machinery among trypanosomatid parasites.

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