Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania

Tanu Rana, Smita Misra, Mukul K. Mittal, Anitra L. Farrow, Keith T. Wilson, MacRae F. Linton, Sergio Fazio, Ian M. Willis, Gautam Chaudhuri

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The parasitic protozoan Leishmania invades mammalian macrophages to establish infection. We reported previously that Leishmania manipulates the expression of several noncoding RNA genes (e.g. Alu RNA, B1 RNA, and signal recognition particle RNA) in macrophages to favor the establishment of their infection in the phagolysosomes of these cells (Ueda, Y., and Chaudhuri, G. (2000) J. Biol. Chem. 275, 19428-19432; Misra, S., Tripathi, M. K., and Chaudhuri, G. (2005) J. Biol. Chem. 280, 29364-29373). We report here the mechanism of this down-regulation. We found that the non-coding RNA (ncRNA) genes that are repressed by Leishmania infection in macrophages contain a "B-box" in their promoters and thus require the polymerase III transcription factor TFIIIC for their expression. We also found that Leishmania promastigotes through their surface protease (leishmanolysin or gp63) activate the thrombin receptor PAR1 in the macrophages. This activation of PAR1 raised the cytosolic concentration of Ca2+ into the micromolar range, thereby activating the Ca2+-dependent protease μ-calpain. μ-Calpain then degraded TFIIIC110 to inhibit the expression of the selected ncRNA genes. Avirulent stocks of Leishmania not expressing surface gp63 failed to down-regulate ncRNAs in the exposed macrophages. Inhibition of PAR1 or calpain 1 in macrophages made them resistant to Leishmania infection. These data suggest that macrophage PAR1 and calpain 1 are potential drug targets against leishmaniasis.

Original languageEnglish (US)
Pages (from-to)6614-6626
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number8
DOIs
StatePublished - Feb 25 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Rana, T., Misra, S., Mittal, M. K., Farrow, A. L., Wilson, K. T., Linton, M. F., Fazio, S., Willis, I. M., & Chaudhuri, G. (2011). Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. Journal of Biological Chemistry, 286(8), 6614-6626. https://doi.org/10.1074/jbc.M110.181735