Cell communication and protein degradation: All in one parasitic package

Abstract

A parasite is a unicellular or multicellular organism that is dependent on another organism (host) for its survival and proliferation. The parasite benefits from a prolonged association with its host (Loker & Hofkin, 2015), as without it, the parasite cannot grow and multiply. Thus, parasites must keep their host alive for as long as possible without killing it, yet their infection may cause diseases and, in some cases, like malaria, even mortality.Three main classes of parasites can cause disease in humans: protozoa, helminths and ectoparasites. The former are unicellular eukaryotic parasites (e.g., Plasmodium falciparum and Trypanosoma brucei), whereas the helminths are parasitic worms (e.g., Schistosoma haematobium and Fasciola hepatica), and the ectoparasites, organisms that infest the host skin (e.g., Haemaphysalis longicornis and Sarcoptes scabiei). These classes of parasites are master manipulators whose life cycles feature unique adaptions, involving sophisticated strategies to alter the host environment, including the secretion of multipurpose extracellular vesicles (EVs) (Coakley et al., 2015;Ofir-Birin & Regev-Rudzki, 2019).EVs are heterogeneous in terms of size (30-500 nm in diameter) and transfer functional signals to target cells by carrying a cornucopia of different molecules, such as proteins, glycans, lipids, RNA and DNA (Schorey et al., 2015;Tkach & Théry, 2016). Since the release of EVs is an integral part of a parasite's life cycle and course of the infection, it stands to reason that these organelles are essential for their survival. Indeed, these shuttling vesicles provide a robust delivery system to facilitate parasitic growth and development, the transfer of virulence factors, adherence to host tissues, and evasion of immune responses (Mardahl et al., 2019;Ofir-Birin et al., 2017). They effectively manipulate the host's immune system by inhibiting or activating responses as well as by affecting a variety of other (non-immune) target human cells (

Malaria parasites release vesicle subpopulations with signatures of different destinations

“…Among the human host proteins, many enzymes involved in cell signaling, endocytosis and cell motility were identified (Fig EV2A and B). Notably, proteolysis related proteins were more prevalent in the F4-EVs (Fig 4C ) including proteasome subunits (PSMB6, PSMA5, VCP and PSMA1) and these results are in line with a previous study which found that the 20S proteasome complexes are encapsulated within Pf-derived EVs (Dekel et al, 2021;Sharon & Regev-Rudzki, 2021). We also identified within the EVs, ESCRT proteins (HGS, STAM) and proteins involved in metabolic processes (APEH, VCP, TPP2, UBC).…”

Systematic identification of 20S proteasome substrates

“…This observation likely explains the nuclear localization of the majority of the substrates. Other interesting functions included cadherin-binding proteins and proteins containing leucine zipper domains, which are both unstructured in the absence of a binding partner (Shapiro and Weis, 2009 ; Vancraenenbroeck and Hofmann, 2018 ), in line with the fact that proteins containing IDRs are frequently involved in mediating interactions.…”

Chloroquine induces eryptosis inP. falciparum-infectedred blood cells and the release of extracellular vesicles with a unique protein profile

“…The 26S proteasome is ATP-dependent and requires ubiquitin-tagged substrates, meanwhile, the 20S proteasome is ubiquitin- and ATP-independent (32). Interestingly, proteasome subunits have been identified in EVs secreted by other protozoa, helminths and ectoparasites (33). For example, in the protozoa Acanthamoeba castellanii the proteasome is involved in the regulation of encystation and extracellular proteolytic activities (34); whereas in Trichinella spiralis the proteasome subunit beta type-7 (PST) has been expressed at different developmental stages and is responsible for a decrease of 45.7% adult worm burden in mice suggesting PST as vaccine antigen against the parasite infection (35).…”