Abstract
The parasitic protozoan Leishmania invades mammalian macrophages to establish infection. We reported previously that Leishmania manipulates the expression of several non-coding 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 Ca(2+) into the micromolar range, thereby activating the Ca(2+)-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.
Highlights
Leishmaniasis is a multisyndrome, debilitating, and often fatal disease affecting millions of people in 88 countries [1,2,3]
We found that the non-coding RNA genes that are repressed by Leishmania infection in macrophages contain a “B-box” in their promoters and require the polymerase III transcription factor TFIIIC for their expression
We found that the genes of the non-coding RNA (ncRNA) that are down-regulated by Leishmania in the infected macrophages are transcribed by RNA polymerase III and are dependent on the transcription factor TFIIIC, its subunit TFIIIC110 [13, 14]
Summary
Leishmaniasis is a multisyndrome, debilitating, and often fatal disease affecting millions of people in 88 countries [1,2,3]. 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 require the polymerase III transcription factor TFIIIC for their expression. We found that Leishmania infection of macrophages down-regulates 7SL RNA gene expression and decreases the levels of selected other ncRNA
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