The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

Abstract

The endoplasmic reticulum (ER) of higher eukaryotic cells forms an intricate membranous network that serves as the main processing facility for folding and assembling of secreted and membrane proteins. The ER is a highly dynamic organelle that interacts with other intracellular structures, as well as endosymbiotic pathogenic and non-pathogenic microorganisms. A strict ER quality control (ERQC) must work to ensure that proteins entering the ER are folded and processed correctly. Unfolded or misfolded proteins are usually identified, selected, and addressed to Endoplasmic Reticulum-Associated Degradation (ERAD) complex. Conversely, when there is a large demand for secreted proteins or ER imbalance, the accumulation of unfolded or misfolded proteins activates the Unfold Protein Response (UPR) to restore the ER homeostasis or, in the case of persistent ER stress, induces the cell death. Pathogenic trypanosomatids, such as Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp are the etiological agents of important neglected diseases. These protozoans have a complex life cycle alternating between vertebrate and invertebrate hosts. The ER of trypanosomatids, like those found in higher eukaryotes, is also specialized for secretion, and depends on the ERAD and non-canonical UPR to deal with the ER stress. Here, we reviewed the basic aspects of ER biology, organization, and quality control in trypanosomatids. We also focused on the unusual way by which T. cruzi, T. brucei, and Leishmania spp. respond to ER stress, emphasizing how these parasites’ ER-unrevealed roads might be an attractive target for chemotherapy.

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

“…Tsetse flies ( Glossina spp) represent the intermediate hosts of T. brucei , while T. cruzi is mainly transmitted by contact with faeces/urine of infected bugs of the triatomine family. Trypanosomatids are hence transferred to the final vertebrate hosts during the insect´s blood meal [ 29 ]. Alongside the heteroxenous life cycle entailing a definitive host and an intermediate host (indirect life cycle), parasites belonging to the Trypanosomatidae family also share some peculiar structural characteristics, namely a single flagellum and a kinetoplast, an organelle containing a large massed mitochondrial DNA [ 28 ].…”

“…Metacyclic trypomastigotes differentiate into amastigotes within the host cells and replicate; then, the intracellular amastigotes assume the form of non-replicative trypomastigotes that cause host cell lysis. Non-replicative bloodstream trypomastigotes could re-enter the triatomine vector midgut and regenerate epimastigotes [ 29 ].…”