Schulze Jana, Kwiatkowski Marcel, Borner Janus, Schlüter Hartmut, Bruchhaus Iris, Burmester Thorsten, Spielmann Tobias, Pick Christian
University of Hamburg, Institute of Zoology, Martin-Luther-King-Platz 3, D-20146, Hamburg, Germany.
Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
Mol Microbiol. 2015 Jul;97(2):301-14. doi: 10.1111/mmi.13024. Epub 2015 May 9.
The pathogenicity of Plasmodium falciparum is partly due to parasite-induced host cell modifications. These modifications are facilitated by exported P. falciparum proteins, collectively referred to as the exportome. Export of several hundred proteins is mediated by the PEXEL/HT, a protease cleavage site. The PEXEL/HT is usually comprised of five amino acids, of which R at position 1, L at position 3 and E, D or Q at position 5 are conserved and important for export. Non-canonical PEXEL/HTs with K or H at position 1 and/or I at position 3 are presently considered non-functional. Here, we show that non-canonical PEXEL/HT proteins are overrepresented in P. falciparum and other Plasmodium species. Furthermore, we show that non-canonical PEXEL/HTs can be cleaved and can promote export in both a REX3 and a GBP reporter, but not in a KAHRP reporter, indicating that non-canonical PEXEL/HTs are functional in concert with a supportive sequence environment. We then selected P. falciparum proteins with a non-canonical PEXEL/HT and show that some of these proteins are exported and that their export depends on non-canonical PEXEL/HTs. We conclude that PEXEL/HT plasticity is higher than appreciated and that non-canonical PEXEL/HT proteins cannot categorically be excluded from Plasmodium exportome predictions.
恶性疟原虫的致病性部分归因于寄生虫诱导的宿主细胞修饰。这些修饰由输出的恶性疟原虫蛋白促成，这些蛋白统称为输出组。数百种蛋白的输出由PEXEL/HT（一种蛋白酶切割位点）介导。PEXEL/HT通常由五个氨基酸组成，其中第1位的R、第3位的L以及第5位的E、D或Q是保守的且对输出很重要。目前认为第1位为K或H和/或第3位为I的非经典PEXEL/HT无功能。在此，我们表明非经典PEXEL/HT蛋白在恶性疟原虫和其他疟原虫物种中过度存在。此外，我们表明非经典PEXEL/HT可被切割，并且在REX3和GBP报告基因中均可促进输出，但在KAHRP报告基因中不行，这表明非经典PEXEL/HT在与支持性序列环境协同作用时具有功能。然后我们选择了具有非经典PEXEL/HT的恶性疟原虫蛋白，并表明其中一些蛋白可输出且其输出依赖于非经典PEXEL/HT。我们得出结论，PEXEL/HT的可塑性比预期的更高，并且非经典PEXEL/HT蛋白不能从疟原虫输出组预测中被绝对排除。
