A model of the diversity and evolution of protein secretion pathways across Apicomplexa, mediated by PEXEL-like sequences. The ancestral apicomplexan PEXEL-mediated trafficking pathway targets proteins to specific secretory organelles as a prelude to achieving secretion beyond the parasite plasma membrane. Organellar targeting in several branches of the phylum uses a PEXEL or PLM for this purpose, suggesting an ancient origin for this signal (red arrowhead). The motif serves to target proteins to secretory organelles for subsequent trafficking to the PVM or beyond. In Toxoplasma such proteins are indeed targeted to the PVM via dense granules, in the absence of additional machinery for further translocation into the host cell. In Babesia, proteins are targeted via spherical bodies to the erythrocytic compartment due to rapid degradation of the host-derived PVM. Retention of the PVM by Plasmodium required acquisition of a dedicated translocon apparatus (blue hexagons) to achieve export across the PVM to access the erythrocyte compartment. In Toxoplasma and Plasmodium, and likely in Babesia as well, the PEXEL(-like) motif represents a proteolytic cleavage site. It should be noted that additional pathways are likely to exist for proteins such as PfEMP1 and VESA1, which remain uncleaved. Pellé KG, Jiang RH, Mantel PY, Xiao YP, Hjelmqvist D, Gallego-Lopez GM, O T Lau A, Kang BH, Allred DR, Marti M. Shared elements of host-targeting pathways among apicomplexan parasites of differing lifestyles. Cell Microbiol. 2015 PMID: 25996544.