Abstract
MSP (GP63) and PSA (GP46) are abundant 63- and 46-kDa glycolipid-anchored proteins on the surface of the promastigote form of most Leishmania species. MSP is a zinc metalloprotease that confers resistance to host complement-mediated lysis. PSA contains internal repeats of 24 amino acids, and its function is unknown. The steady state levels of mRNAs for both glycoproteins are regulated post-transcriptionally, resulting in about a 30-fold increase as Leishmania chagasi promastigotes grow in vitro from logarithmic phase to stationary phase. Previous studies showed the 3'-untranslated regions (3'-UTRs) of these mRNAs are essential for this post-transcriptional regulation. These two 3'-UTRs of 1.0 and 1.3 kilobases were cloned immediately downstream of a beta-galactosidase reporter gene in a plasmid, and segments were systematically deleted to examine which portions of the 3'-UTRs contribute to the post-transcriptional regulation. The 92-nucleotide segment of greatest similarity between the two 3'-UTRs was deleted without loss of regulation, but the segments flanking this similarity region have positive regulatory elements essential for the regulation. We propose that similar, but non-identical, molecular mechanisms regulate the parallel expression of these two L. chagasi mRNAs despite their lack of sequence identity. These post-transcriptional mechanisms resemble the mechanism recently suggested for the regulation of mRNAs encoding the dipeptide (EP) and pentapeptide (GPEET) repeat proteins in Trypanosoma brucei that involves interactions between positive and negative regulatory elements in the 3'-UTR.
Highlights
In Leishmania chagasi, which causes visceral leishmaniasis in Latin America, MSP is encoded by more than 18 genes (MSPs) that fall into three classes on the basis of (i) the stage at which they are expressed in the life cycle and (ii) unique sequences in their 3Ј-untranslated regions (UTRs) and intergenic regions (IRs) [13]
We discovered that the regions immediately flanking this 92-nucleotide segment are involved in regulating the levels of both the MSPS and PSA genes (PSAs) mRNAs through similar, but non-identical, mechanisms
FIG. 1. 3-untranslated regions (3-UTRs) and IR swapping experiments showing that cis-regulatory elements reside in the 3-UTR of PSAA, not the IR
Summary
Leishmania and other trypanosomatids do not appear to have promoters for RNA polymerase II, which transcribes protein-encoding genes, even though transcription of these genes is sensitive to ␣-amanitin as it is in other eukaryotes [21] Instead, these genes are constitutively transcribed from large gene clusters, and the steady state levels of their mature mRNAs are regulated post-transcriptionally by mechanisms that often involve their 3Ј-UTR sequences [22,23,24,25,26,27,28]. We discovered that the regions immediately flanking this 92-nucleotide segment are involved in regulating the levels of both the MSPS and PSA mRNAs through similar, but non-identical, mechanisms These mechanisms have features in common with a recently proposed model for the regulation of the Trypanosoma brucei genes for EP and GPEET, the most abundant proteins on the surface of the insect form of African trypanosomes (29 –32)
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