Exploring Leishmania linear motifs directing protein secretion, sorting and autophagy

ABSTRACT The pathogenic tropical flagellates Leishmania belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Here, we explore three ancient protein targeting linear motif systems and their receptors and demonstrate how they resemble or differ from other eukaryotic organisms, including their hosts. Secretory signal peptides, endoplasmic reticulum (ER) retention motifs (KDEL motifs), and autophagy signals (motifs interacting with ATG8 family members) are essential components of cellular life. Although expected to be conserved, we observe that all three systems show a varying degree of divergence from the eukaryotic version observed in animals, plants, or fungi. We not only describe their behavior but also build predictive models that allow the prediction of localization or function for several proteins in Leishmania species for the first time. Several of these critical protein-protein interactions could serve as targets of selective antimicrobial agents against Leishmaniasis due to their divergence from the host.