Abstract
Trichomonas vaginalis is an extracellular eukaryotic parasite that causes the most common, non-viral sexually transmitted infection worldwide. Although disease burden is high, molecular mechanisms underlying T. vaginalis pathogenesis are poorly understood. Here, we identify a family of putative T. vaginalis rhomboid proteases and demonstrate catalytic activity for two, TvROM1 and TvROM3, using a heterologous cell cleavage assay. The two T. vaginalis intramembrane serine proteases display different subcellular localization and substrate specificities. TvROM1 is a cell surface membrane protein and cleaves atypical model rhomboid protease substrates, whereas TvROM3 appears to localize to the Golgi apparatus and recognizes a typical model substrate. To identify TvROM substrates, we interrogated the T. vaginalis surface proteome using both quantitative proteomic and bioinformatic approaches. Of the nine candidates identified, TVAG_166850 and TVAG_280090 were shown to be cleaved by TvROM1. Comparison of amino acid residues surrounding the predicted cleavage sites of TvROM1 substrates revealed a preference for small amino acids in the predicted transmembrane domain. Over-expression of TvROM1 increased attachment to and cytolysis of host ectocervical cells. Similarly, mutations that block the cleavage of a TvROM1 substrate lead to its accumulation on the cell surface and increased parasite adherence to host cells. Together, these data indicate a role for TvROM1 and its substrate(s) in modulating attachment to and lysis of host cells, which are key processes in T. vaginalis pathogenesis.
Highlights
Trichomonas vaginalis is an extracellular, eukaryotic parasite that is the causative agent of trichomoniasis, the most common non-viral sexually transmitted infection in the world [1]
We report the first characterization of T. vaginalis intramembrane rhomboid proteases
We further identified two TvROM1 substrates, one of which we demonstrate is involved in modulating host: parasite interactions
Summary
Trichomonas vaginalis is an extracellular, eukaryotic parasite that is the causative agent of trichomoniasis, the most common non-viral sexually transmitted infection in the world [1]. 276 million people worldwide become newly infected each year [1]. In the United States, an estimated 3.7 million people are currently infected [2]. T. vaginalis is associated with cervical cancer [10, 11] and aggressive prostate cancer [12, 13]. Due to the high burden, threat of illness, and understudied nature of T. vaginalis infection, trichomoniasis has been recently recognized as one of the United States’ neglected parasitic infections [4, 14, 15]
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