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The mitochondrial SIR2 related protein 2 (SIR2RP2) impacts Leishmania donovani growth and infectivity

Nimisha Mittal1, Rohini Muthuswami2, Rentala Madhubala1

  • 1School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

Plos Neglected Tropical Diseases
|May 12, 2017
PubMed
Abstract

Insights

Leishmania donovani SIR2RP2, an enzyme, exhibits ADP-ribosyltransferase activity and is crucial for parasite survival and infectivity. Targeting this sirtuin offers a promising strategy for developing new visceral leishmaniasis drugs.

Area of Science:

  • Parasitology
  • Molecular Biology
  • Biochemistry

Background:

  • Visceral leishmaniasis is caused by the protozoan parasite Leishmania donovani.
  • Existing drugs for leishmaniasis face challenges of toxicity and drug resistance.
  • Sirtuins (Silent Information Regulator proteins) are emerging as potential drug targets in kinetoplastids.

Purpose of the Study:

  • To functionally characterize the Leishmania donovani SIR2 related protein 2 (LdSIR2RP2).
  • To investigate the potential of LdSIR2RP2 as a drug target for visceral leishmaniasis.

Main Methods:

  • Recombinant LdSIR2RP2 was expressed, purified, and its enzymatic activities assessed.
  • Subcellular localization was determined using a GFP-tagged construct.
  • Gene deletion mutants (null mutants) were created and analyzed for growth, virulence, cell cycle, mitochondrial function, and drug sensitivity.

Main Results:

  • LdSIR2RP2 demonstrated NAD+-dependent ADP-ribosyltransferase activity but lacked deacetylase and desuccinylase functions.
  • The protein was localized to the mitochondrion in Leishmania promastigotes.
  • Null mutants exhibited restricted growth, G2/M phase cell cycle arrest, impaired mitochondrial function, and reduced infectivity.
  • Deletion of LdSIR2RP2 increased parasite sensitivity to sirtuin inhibitors, which also inhibited the recombinant enzyme's activity.

Conclusions:

  • LdSIR2RP2 is a functional enzyme with ADP-ribosyltransferase activity, essential for Leishmania donovani proliferation, mitochondrial function, and infectivity.
  • Targeting LdSIR2RP2, a sirtuin, presents a viable strategy for developing novel therapeutic interventions against visceral leishmaniasis.

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