Unconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes

Abstract

In addition to conventional protein secretion, dependent on the specific cleavage of signal sequences, proteins are secreted by other processes, all together called unconventional. Among the mechanisms operative in unconventional secretion, some are based on two families of extracellular vesicle (EVs), expressed by all types of cells: the exosomes (before secretion called ILVs) and ectosomes (average diameters ∼70 and ∼250 nm). The two types of EVs have been largely characterized by extensive studies. ILVs are assembled within endocytic vacuoles by inward budding of small membrane microdomains associated to cytosolic cargos including unconventional secretory proteins. The vacuoles containing ILVs are called multivesicular bodies (MVBs). Upon their possible molecular exchange with autophagosomes, MVBs undergo two alternative forms of fusion: 1. with lysosomes, followed by large digestion of their cargo molecules; and 2. with plasma membrane (called exocytosis), followed by extracellular diffusion of exosomes. The vesicles of the other type, the ectosomes, are differently assembled. Distinct plasma membrane rafts undergo rapid outward budding accompanied by accumulation of cytosolic/secretory cargo molecules, up to their sewing and pinching off. Both types of EV, released to the extracellular fluid in their complete forms including both membrane and cargo, start navigation for various times and distances, until their fusion with target cells. Release/navigation/fusion of EVs establish continuous tridimensional networks exchanging molecules, signals and information among cells. The proteins unconventionally secreted via EVs are a few hundreds. Some of them are functionally relevant (examples FADD, TNF, TACE), governing physiological processes and important diseases. Such proteins, at present intensely investigated, predict future discoveries and innovative developments, relevant for basic research and clinical practice.

Unconventional protein secretion (UPS): role in important diseases

“…The task is to provide knowledge and understanding at least useful for the presentation of diseases and their therapy appearing in the subsequent Sections. In case of UPS details lacking here, they can be easily found in other reviews, appeared during the last few years [ 8 , 16 – 18 ].…”

“…1 . In this process the vesicular R-SNARE protein most frequently involved is VAMP7, which in contrast is inactive or marginal in the exocytosis of other organelles [ 17 , 18 ]. The processes of endo-lysosomes and APhs are rare whereas those of exosomes are much more frequent.…”

“…This makes impossible their conventional secretion, which is replaced by fluid and solid forms of UPS. Proteins initially accumulated by organelles of the 3 or 4 types are numerous [ 17 , 18 ]. Moreover, the identification of their markers is important [ 47 , 48 ].…”

“…Studies started at the end of 1990, then extended and now widely accepted, demonstrate that two additional, 3 and 4 type secretions are solid components originated from specific intracellular organelles distinct from those of conventional secretion [ 15 , 16 ]. Important properties of the four types of UPS in healthy cells and organs, initially proposed years ago [ 11 , 15 , 16 ], were confirmed according to general data and criteria [ 7 , 8 , 17 , 18 ]. Recently, therefore, interest about UPS has increased considerably, approaching the levels existing since decades for conventional secretion.…”

“…Other recent UPS reviews included no diseases [ 7 , 16 ] or only few details about them [ 17 ]. In my recent review diseases were lacking [ 18 ], however their general presentation was expected to appear in a coming article. In the recent literature, general view of UPS-dependent diseases had been reported only in two cases appeared in 2018 and 2019 [ 22 , 23 ].…”