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.
Highlights
A protein destined to be secreted carries a signal peptide or signal leader sequence and is often transported from the endoplasmic reticulum (ER) to the Golgi apparatus, to the trans-Golgi network for sorting, and to the plasma membrane via vesicular carriers (Palade, 1975; Rothman, 1994)
This study suggests that the described vesicular structure corresponds to the ER–Golgi intermediate compartment (ERGIC), and IL-1β is transported into this compartment via a TMED10-mediated protein channel (Zhang et al, 2020)
In a study by Evavold et al (2018), gasdermin D pores were shown to be necessary for IL-1β transport across an intact plasma membrane of living macrophages. This suggests that gasdermin D is responsible for passive interleukin secretion during pyroptosis and for its active transport in living cells (Heilig et al, 2017; Evavold et al, 2018; Lieberman et al, 2019). Even though this mode of secretion via pores has similarities with the unconventional protein secretion” (UPS) type I route, which was mainly studied in fibroblast growth factor 2 (FGF2), neither pro-IL-1β nor mature IL-1β was found to bind to membranes (Martín-Sánchez et al, 2016); the transport is not mediated by the substrate itself
Summary
A protein destined to be secreted carries a signal peptide or signal leader sequence and is often transported from the ER to the Golgi apparatus, to the trans-Golgi network for sorting, and to the plasma membrane via vesicular carriers (Palade, 1975; Rothman, 1994). UPS type I is probably the best characterized and was mainly elucidated using fibroblast growth factor 2 (FGF2) as its model substrate (Wegehingel et al, 2008; La Venuta et al, 2015; Steringer et al, 2015; Legrand et al, 2020) In this secretion pathway, the leaderless substrate is translocated to the extracellular space with self-sustained formation of pores in the plasma membrane. UPS route type IV is the only known UPS pathway, which includes substrates presenting a leader sequence These substrates are trafficked through the ER, but bypass the Golgi on their way to the plasma membrane (Gee et al, 2018; Kim et al, 2018). Involved in the most central mechanisms of disease such as inflammation and cancer cell proliferation and, for this review, secretion of virulence factors in parasites, it is of crucial importance
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