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Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
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Myotubularin-related protein 6 is an ion channel-associated pro-leishmanial phosphatase

Shabina Parveen1, Saikat Majumder1, Neelam Bodhale2

  • 1Department of Molecular Medicine, Bose Institute, CIT Scheme VII-M, Kolkata 700054. India.

International Immunopharmacology
|February 8, 2024
PubMed

Insights

Myotubularin-related protein-6 (MTMR6) is identified as a key phosphatase in visceral leishmaniasis (VL). Silencing MTMR6 reduces parasite load and IL-10, offering new therapeutic targets for this re-emerging disease.

Area of Science:

  • Immunology
  • Parasitology
  • Molecular Biology

Background:

  • Visceral leishmaniasis (VL) is a fatal, re-emerging disease caused by *Leishmania donovani* parasites residing in macrophages.
  • Intracellular signaling, modulated by kinases and phosphatases, is crucial for VL pathogenesis.
  • The specific phosphatases influencing VL outcomes in humans were previously unknown.

Purpose of the Study:

  • To identify phosphatases that modulate visceral leishmaniasis (VL) outcomes in human macrophages.
  • To investigate the role of myotubularin-related protein-6 (MTMR6) in *Leishmania donovani* infection.

Main Methods:

  • Screening of a human phosphatase siRNA library in THP-1 macrophage-like cells infected with *L. donovani*.
  • Analysis of MTMR6 expression in macrophages following infection, Toll-like receptor (TLR2) stimulation/blockade, and miltefosine treatment.
  • Comparison of MTMR6 expression in VL patients and endemic controls.

Main Results:

  • Myotubularin-related protein-6 (MTMR6) was identified as the sole phosphatase whose silencing reduced *L. donovani* load and IL-10 production.
  • Virulent *L. donovani* infection and TLR2 stimulation increased MTMR6 expression, while TLR2 blockade and miltefosine treatment reduced it.
  • Untreated VL patients exhibited higher MTMR6 levels compared to endemic controls, with levels reduced upon miltefosine treatment.

Conclusions:

  • MTMR6 is the first identified ion channel-associated phosphatase modulated by TLR2 signaling with significant implications in VL.
  • MTMR6 plays a critical role in *Leishmania donovani* infection and visceral leishmaniasis pathogenesis.
  • Targeting MTMR6 presents a potential therapeutic strategy for visceral leishmaniasis.
Keywords:
Cell signalingIon-ChannelLeishmaniaMTMRMacrophagesPhosphatase

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