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Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: the Autophagic- and Endo-Lysosomal Systems Go Extracellular

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Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: the Autophagic- and Endo-Lysosomal Systems Go Extracellular International Journal of Molecular Sciences Review Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular 1, 1, 1,2 1 3 Sandra Buratta y, Brunella Tancini y, Krizia Sagini , Federica Delo , Elisabetta Chiaradia , Lorena Urbanelli 1,* and Carla Emiliani 1,4,* 1 Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy; [email protected] (S.B.); [email protected] (B.T.); [email protected] (K.S.); [email protected] (F.D.) 2 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Montebello, Oslo, Norway 3 Department of Veterinary Medicine, University of Perugia, Via S. Costanzo 4, 06126 Perugia, Italy; [email protected] 4 Centro di Eccellenza sui Materiali Innovativi Nanostrutturati (CEMIN), University of Perugia, Via del Giochetto, 06123 Perugia, Italy * Correspondence: [email protected] (L.U.); [email protected] (C.E.); Tel.: +39-075-585-7440 (L.U.); +39-075-585-7438 (C.E.); Fax: +39-075-585-7436 (L.U. & C.E.) Both authors contributed equally to this work. y Received: 17 March 2020; Accepted: 6 April 2020; Published: 8 April 2020 Abstract: Beyond the consolidated role in degrading and recycling cellular waste, the autophagic- and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic- and endo-lysosomal systems, evaluating their implication in health and disease. Keywords: lysosomal exocytosis; exosomes; extracellular vesicles; secretory autophagy; autophagosomes; amphisomes; unconventional protein secretion Int. J. Mol. Sci. 2020, 21, 2576; doi:10.3390/ijms21072576 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 2576 2 of 20 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 19 1. Introduction 1. Introduction Lysosomes are terminal degradative organelles whose functions are fundamental to maintain cell Lysosomes are terminal degradative organelles whose functions are fundamental to maintain homeostasis, but there is evidence that the content of lysosomes and of organelles of the autophagic- cell homeostasis, but there is evidence that the content of lysosomes and of organelles of the and endo-lysosomal system can be poured out the cell, contributing to cellular clearance and cell-to-cell autophagic- and endo-lysosomal system can be poured out the cell, contributing to cellular clearance communication. Lysosomal exocytosis leads to the secretion of lysosomal content upon fusion of and cell-to-cell communication. Lysosomal exocytosis leads to the secretion of lysosomal content lysosomes with the plasma membrane. This allows to accomplish important functions, such as plasma upon fusion of lysosomes with the plasma membrane. This allows to accomplish important functions, membrane repair and tissue remodeling. Current investigations also provide evidence that organelles such as plasma membrane repair and tissue remodeling. Current investigations also provide delivering cell material to lysosomes for degradation, such as autophagosome and endosomes, evidence that organelles delivering cell material to lysosomes for degradation, such as can change their destination from fusion with lysosomes to fusion with plasma membrane for autophagosome and endosomes, can change their destination from fusion with lysosomes to fusion extracellular release. From a functional point of view, this alternative route appears to be not only an with plasma membrane for extracellular release. From a functional point of view, this alternative additional manner to dispose waste, but a process finely tuned which is relevant for the unconventional route appears to be not only an additional manner to dispose waste, but a process finely tuned which protein secretion of signaling molecules, for the release of vesicles originating in late endosomes is relevant for the unconventional protein secretion of signaling molecules, for the release of vesicles (exosomes), which are now considered an additional manner of cell-to-cell communication, and for originating in late endosomes (exosomes), which are now considered an additional manner of cell- immune surveillance of pathogens (Figure1). In this review, we summarize the current knowledge on to-cell communication, and for immune surveillance of pathogens (Figure 1). In this review, we lysosomal exocytosis, exosome release and secretory autophagy to shed light on the functional role summarize the current knowledge on lysosomal exocytosis, exosome release and secretory and pathological implications of the extracellular release of lysosomes and other organelles of the autophagy to shed light on the functional role and pathological implications of the extracellular autophagic- and endo-lysosomal system. release of lysosomes and other organelles of the autophagic- and endo-lysosomal system. Figure 1. Overview of lysosomal exocytosis, exosome release and autophagy-dependent secretory Figure 1. Overview of lysosomal exocytosis, exosome release and autophagy-dependent secretory pathways. Lysosomal exocytosis leads to the secretion of lysosomal content upon lysosome fusion pathways. Lysosomal exocytosis leads to the secretion of lysosomal content upon lysosome fusion with plasma membrane. Exosomes originate from the inward budding of late endosome membrane, with plasma membrane. Exosomes originate from the inward budding of late endosome membrane, which originates MVBs. They are either released extracellularly upon exocytosis or degraded into lysosomes. which originates MVBs. They are either released extracellularly upon exocytosis or degraded into Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their lysosomes. However, the autophagic machinery is also involved in autophagy-dependent secretion of degradation within lysosomes. However, the autophagic machinery is also involved in autophagy- autophagosomes. In addition to merging with lysosomes or plasma membrane, autophagosomes can dependent secretion of autophagosomes. In addition to merging with lysosomes or plasma also fuse with late endosomes/MVBs to produce amphisomes. In turn, amphisomes can either fuse with membrane, autophagosomes can also fuse with late endosomes/MVBs to produce amphisomes. In lysosomes to degrade their content or with plasma membrane. The red arrows indicate fusion with turn, amphisomes can either fuse with lysosomes to degrade their content or with plasma membrane. plasma membrane, the green arrows, fusion with lysosome, and the black arrows, pathways leading to The red arrows indicate fusion with plasma membrane, the green arrows, fusion with lysosome, and organelle maturation and to the intersection between autophagic and endocytic pathway. the black arrows, pathways leading to organelle maturation and to the intersection between 2. Lysosomalautophagic Exocytosis and endocytic pathway. In recent decades, it has been clearly demonstrated that lysosomes can accomplish a secretory 2. Lysosomal Exocytosis pathway known as lysosomal exocytosis [1,2]. At first, lysosomal exocytosis was regarded as a functionIn recent of specialized decades, it secretory has been cells, clearly namely demonstrated hematopoietic that lysosomes cells, containing can accomplish a peculiar a secretory type of pathway known as lysosomal exocytosis [1,2]. At first, lysosomal exocytosis was regarded as a function of specialized secretory cells, namely hematopoietic cells, containing a peculiar type of lysosomes, which acquired the competence of regulated secretory organelles (secretory lysosomes). Int. J. Mol. Sci. 2020, 21, 2576 3 of 20 lysosomes, which acquired the competence of regulated secretory organelles (secretory lysosomes).
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