![]() In addition, biomolecules associated with various diseases, including cancer, neurodegenerative diseases, such as Parkinson’s, Alzheimer’s and transmissible spongiform encephalopathies (prion disease), and inflammatory disorders have been identified in exosomes.īiogenesis and secretion of ectosomes. Generally, proteins involved in MVB formation, tetraspanins, membrane transport and fusion, transmembrane proteins, cytoskeletal components and proteins of cytosolic origin are part of exosomes. The now formed MVB is transported to the PM and through fusion, the ILVs are released into the extracellular environment and are now called “exosomes” ( B) Exosomal luminal cargo predominantly consists of mRNA, miRNA and gDNA fragments, and a myriad of different proteins depending on the cell of origin. DUBs deubiquitinate the protein and Vps4 recycles the ESCRT machinery. ESCRT-I and -II drive budding of ILVs, during which cargo is transported into the lumen, and ESCRT-III is recruited by Alix to complete budding and drive vesicle scission (spiral formation and pulling). In the ESCRT-dependent pathway, components of the ESCRT machinery are sequentially recruited to the endosomal membrane, which starts with Hrs, and bind to phosphatidylinositol-3-phosphate (PI(3) P) and the 3,5-bisphosphate (PI(3,5) P2) through lipid binding domains (e.g., FYVE, GLUE), and to the ubiquitinated protein (ESCRT-0). ![]() These ceramide-enriched domains have structural imbalances between monoleaflets causing the membrane to bend inward. The ceramide-dependent pathway is based on the formation of lipid rafts in which sphingomyelin is converted to ceramide by sphingomyelinases. ( A) The biogenesis and secretion of exosomes is believed to be mediated via a ceramide and/or ESCRT-dependent pathway. Exosomal cargo delivery to the recipient cell can occur through various mechanisms, i.e., direct fusion with the recipient cell’s membrane, pinocytosis/phagocytosis, or ligand–receptor binding.īiogenesis, secretion and composition of exosomes. ![]() This pathway is particularly important for restricting signaling by activated growth factor receptors. In the exocytic pathway ①, MVBs fuse with the PM to release their contents (exosomes) into the extracellular space In the degradative pathway ②, the MVBs are trafficked to lysosomes for enzyme-assisted degradation. Formation of exosomes starts with inward budding of the early endosome’s membrane and subsequent formation of MVBs. ![]() In early endosomes, proteins are either recycled to the PM or sequestered into the intraluminal vesicles (ILV) of MVBs. #The next big thing 2017 freeCargo is taken up by the cell via endocytosis (receptor-mediated and free uptake) and formation of early endosomes. Various types of cargo, e.g., proteins, RNA, can also be transported into the extracellular space via outward PM budding and formation of shedded vesicles (ectosomes). By fusing with the PM, both membrane proteins and secretory proteins are effectively transported to their intended destinations. In the classical secretory pathway, vesicles with protein cargo, sorted and packed in the Golgi apparatus, transport their cargo to the plasma membrane (PM). ![]() Pathways involving various types of vesicles. #The next big thing 2017 seriesThe "Focus on extracellular vesicles" series of reviews highlights the current state of the art regarding various topics in EV research, whilst this review serves as an introductory overview of EVs, their biogenesis and molecular composition.Īpoptotic body biogenesis ectosome exosome extracellular vesicle isolation microvesicle molecular composition signal transduction. Consequently, the research effort into the pathogenic roles of EVs is significantly higher even though their protective roles are not well established. Additionally, it is now becoming increasingly clear that EVs mediate disease progression and therefore studying EVs has ignited significant interests among researchers from various fields of life sciences. Whilst this is a major function of one type of EV, i.e., apoptotic bodies, many EVs have intricate functions in intercellular communication and compound exchange although their physiological roles are still ill-defined. These "extracellular vesicles" (EV) were initially thought to be garbage bags through which the cell ejected its waste. With the discovery of small secreted vesicular structures that contain complex cargo, both in their lumen and the lipid membrane that surrounds them, a new frontier of signal transduction was discovered. Intercellular communication was long thought to be regulated exclusively through direct contact between cells or via release of soluble molecules that transmit the signal by binding to a suitable receptor on the target cell, and/or via uptake into that cell. ![]()
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