Helminth genome analysis reveals conservation of extracellular vesicle biogenesis pathways but divergence of RNA loading machinery between phyla

Abstract

A comparative genomics approach was used to determine whether established extracellular vesicle (EV) biogenesis pathways are conserved in helminths. This revealed conservation of membrane and cytoskeletal-organising proteins as well as the endosomal sorting complex required for transport (ESCRT) previously described in mammalian cells. Domain-level analysis of this complex in helminths, however, indicated that some species may rely on atypical proteins to support subunit interactions and cargo recruitment. Interestingly, helminths displayed phylum-level divergence of proteins associated with loading RNA into EVs. These findings provide a framework for functional studies of helminth EV biogenesis and cargo sorting.

Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

“…Interestingly, ALIX silencing can affect the exosome composition rather than abscission, so it seems ALIX can affect the cargo or subtypes of MVBs before secretion. Based on some facts, MVB biogenesis could occur in the absence of an ESCRT machinery system [ 51 ]. These data show that ESCRT subsets exhibit a different mechanism of action on exosome biogenesis and secretion [ 52 – 54 ].…”

Helminth extracellular vesicles: Interactions with the host immune system

“…Particles that correspond to the size of both exosomes and microvesicles have been identified in the ES of helminths ( Cwiklinski et al, 2015 ; Hansen et al, 2019 ), though many seem to be exosome-like ( Buck et al, 2014 ; Harischandra et al, 2018 ). The ESCRT machinery required for MVB formation, as well as proteins that participate in microvesicle formation, are conserved in helminths including species where EV release has not yet been reported ( Bennett et al, 2020b ), so helminths certainly seem equipped to make and release EVs of either class. Difficulties in differentiating exact cellular origin lead to the use of the umbrella term ‘EV’.…”

“…Difficulties in differentiating exact cellular origin lead to the use of the umbrella term ‘EV’. Interestingly, 55 EV biogenesis proteins were found in EVs released by platyhelminths, whereas only 7 were found in those released by nematodes ( Bennett et al, 2020b ), hinting at differences in production between the two groups.…”

“…Helminth EVs also contain species of small RNAs, which can play a role in host-helminth interaction ( Sotillo et al, 2020 ; Wu et al, 2019 ; Fromm et al, 2017 ). Proteins implicated in RNA-loading into EVs such as argonaute 2 (Ago2) are conserved in helminths, though there are some differences between phyla ( Bennett et al, 2020b ). Major vault protein (MVP) is conserved solely in platyhelminths and present in their EVs, and there has been a lineage-specific expansion of argonaut proteins (WAGOs) in nematodes ( Bennett et al, 2020b ).…”

“…Proteins implicated in RNA-loading into EVs such as argonaute 2 (Ago2) are conserved in helminths, though there are some differences between phyla ( Bennett et al, 2020b ). Major vault protein (MVP) is conserved solely in platyhelminths and present in their EVs, and there has been a lineage-specific expansion of argonaut proteins (WAGOs) in nematodes ( Bennett et al, 2020b ). A WAGO from H. polygyrus is found associated with small interfering (si)RNAs specifically found within EVs, suggesting a means of selective export ( Chow et al, 2019 ).…”