Abstract
Small ubiquitin-related modifiers (SUMOs) are post-translationally conjugated to other proteins and are thereby essential regulators of a wide range of cellular processes. Sumoylation, and enzymes of the sumoylation pathway, are conserved in the malaria causing parasite, Plasmodium falciparum. However, the specific functions of sumoylation in P. falciparum, and the degree of functional conservation between enzymes of the human and P. falciparum sumoylation pathways, have not been characterized. Here, we demonstrate that sumoylation levels peak during midstages of the intra-erythrocyte developmental cycle, concomitant with hemoglobin consumption and elevated oxidative stress. In vitro studies revealed that P. falciparum E1- and E2-conjugating enzymes interact effectively to recognize and modify RanGAP1, a model mammalian SUMO substrate. However, in heterologous reactions, P. falciparum E1 and E2 enzymes failed to interact with cognate human E2 and E1 partners, respectively, to modify RanGAP1. Structural analysis, binding studies, and functional assays revealed divergent amino acid residues within the E1-E2 binding interface that define organism-specific enzyme interactions. Our studies identify sumoylation as a potentially important regulator of oxidative stress response during the P. falciparum intra-erythrocyte developmental cycle, and define E1 and E2 interactions as a promising target for development of parasite-specific inhibitors of sumoylation and parasite replication.
Highlights
The sumoylation pathway is conserved in Plasmodium falciparum
Sumoylation Peaks during Late Stages of the P. falciparum intra-erythrocyte developmental cycle (IDC)—Genes coding for small ubiquitin-related modifier (SUMO), and enzymes of the sumoylation pathway, have been identified through bioinformatic analysis of the P. falciparum genome [12, 13] (Fig. 1b)
To gain insights into possible stage-specific roles for sumoylation during the IDC, we synchronized P. falciparuminfected red blood cell cultures and performed immunoblot analysis of lysates prepared from purified ring, trophozoite, and schizont stage parasites
Summary
Results: The small ubiquitin-related modifier (SUMO) E1 and E2 enzymes are not functionally interchangable between humans and the malaria parasite, P. falciparum. Our studies identify sumoylation as a potentially important regulator of oxidative stress response during the P. falciparum intra-erythrocyte developmental cycle, and define E1 and E2 interactions as a promising target for development of parasite-specific inhibitors of sumoylation and parasite replication. The functional significance of the modification of these proteins, and the importance of sumoylation in progression through the IDC and protection from oxidative stress, remains to be fully characterized. An inhibitor of desumoylation blocks P. falciparum replication in human red blood cell cultures, demonstrating that sumoylation is essential during the IDC and that inhibitors of the sumoylation pathway have potential as effective anti-malarial drugs [13]. Our findings indicate the E1- and E2-conjugating enzymes of P. falciparum may be viable drug targets, and that inhibitors of SUMO conjugation might prove effective in combination therapies with drugs that enhance oxidative stress, including artemisinin
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