The Road Less Traveled? Unconventional Protein Secretion at Parasite–Host Interfaces

Abstract

Protein secretion in eukaryotic cells is a well-studied process, which has been known for decades and is dealt with by any standard cell biology textbook. However, over the past 20 years, several studies led to the realization that protein secretion as a process might not be as uniform among different cargos as once thought. While in classic canonical secretion proteins carry a signal sequence, the secretory or surface proteome of several organisms demonstrated a lack of such signals in several secreted proteins. Other proteins were found to indeed carry a leader sequence, but simply circumvent the Golgi apparatus, which in canonical secretion is generally responsible for the modification and sorting of secretory proteins after their passage through the endoplasmic reticulum (ER). These alternative mechanisms of protein translocation to, or across, the plasma membrane were collectively termed “unconventional protein secretion” (UPS). To date, many research groups have studied UPS in their respective model organism of choice, with surprising reports on the proportion of unconventionally secreted proteins and their crucial roles for the cell and survival of the organism. Involved in processes such as immune responses and cell proliferation, and including far more different cargo proteins in different organisms than anyone had expected, unconventional secretion does not seem so unconventional after all. Alongside mammalian cells, much work on this topic has been done on protist parasites, including genera Leishmania, Trypanosoma, Plasmodium, Trichomonas, Giardia, and Entamoeba. Studies on protein secretion have mainly focused on parasite-derived virulence factors as a main source of pathogenicity for hosts. Given their need to secrete a variety of substrates, which may not be compatible with canonical secretion pathways, the study of mechanisms for alternative secretion pathways is particularly interesting in protist parasites. In this review, we provide an overview on the current status of knowledge on UPS in parasitic protists preceded by a brief overview of UPS in the mammalian cell model with a focus on IL-1β and FGF-2 as paradigmatic UPS substrates.

Interaction of helminth parasites with the haemostatic system of their vertebrate hosts: a scoping review

“…It is worth mentioning that the vast majority of the reported proteins have been described as having other canonical functions, apart from their participation in the manipulation of the host haemostatic system. This mechanism is referred to as "moonlighting" and constitutes an advantageous parasite strategy of energy saving based on proteins exhibiting "expected or unexpected" functions depending on some factors, such as their different location or secretory pathways [7,26]. In line with this, our results showed that the majority of the interactions were described in surface parasitic extracts and excretory/secretory products, which indicates that parasite molecules involved in the exploitation of the host haemostatic system are mainly expressed on the parasite surface or secreted to their environment from the cytosol.…”

Released Parasite-Derived Kinases as Novel Targets for Antiparasitic Therapies

“…In Leishmania , 98% of the secreted proteins lack SP, suggesting the presence of other secretion pathways ( Silverman et al., 2008 ). The second mechanism is unconventional protein secretion (UPS) and refers to proteins either exposed on the cell surface or in the extracellular medium ( Balmer and Faso, 2021 ). The third mechanism is through extracellular vesicles (EVs), lipid-bound vesicles which either bud from the plasma membrane (microvesicles) or are derived from multivesicular bodies that fuse with the plasma membrane (exosomes) ( Dlugonska and Gatkowska, 2016 ; Mathieu et al., 2019 ; Babatunde et al., 2020 ) and for more details in mechanisms of secretion see ( Teng and Fussenegger, 2021 ).…”

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

“…Moreover, the translocation of GAPDH to the nucleus in response to cellular stress is evidence of GAPDH involvement in nonmetabolic processes in higher eukaryotic cells [49]. When these Leishmania cells were exposed to cellular stress, such as serum withdrawal or stress generated by hydrogen peroxide exposure, no translocation of GFP-cGAPDH fusion proteins into the nucleus was observed.…”