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LAMP2A regulates the loading of proteins into exosomes

View ORCID ProfileJoão Vasco Ferreira, View ORCID ProfileAna da Rosa Soares, José Ramalho, Catarina Máximo Carvalho, Maria Helena Cardoso, Petra Pintado, Ana Sofia Carvalho, Hans Christian Beck, Rune Matthiesen, Mónica Zuzarte, Henrique Girão, View ORCID ProfileGuillaume van Niel, View ORCID ProfilePaulo Pereira
doi: https://doi.org/10.1101/2021.07.26.453637
João Vasco Ferreira
1Proteostasis and Proteolytic Signalling Lab, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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  • ORCID record for João Vasco Ferreira
Ana da Rosa Soares
1Proteostasis and Proteolytic Signalling Lab, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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José Ramalho
1Proteostasis and Proteolytic Signalling Lab, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Catarina Máximo Carvalho
1Proteostasis and Proteolytic Signalling Lab, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Maria Helena Cardoso
1Proteostasis and Proteolytic Signalling Lab, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Petra Pintado
2Fish Facility, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Ana Sofia Carvalho
3Computational and Experimental Biology Group, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Hans Christian Beck
4Centre for Clinical Proteomics, Department of Clinical Biochemistry and Pharmacology, Odense University, Hospital, Odense, Denmark
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Rune Matthiesen
3Computational and Experimental Biology Group, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Mónica Zuzarte
5Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Coimbra, Portugal
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Henrique Girão
5Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Coimbra, Portugal
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Guillaume van Niel
6Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, F-75014 Paris, France
7GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014 Paris, France
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Paulo Pereira
1Proteostasis and Proteolytic Signalling Lab, CEDOC, ChronicDiseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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  • For correspondence: paulo.pereira@nms.unl.pt
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Abstract

Exosomes are extracellular vesicles of endosomal origin released by virtually all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs and proteins between different cells, tissues or organs. However, the mechanisms that regulate the selective loading of cytosolic proteins into these vesicles are still largely unknow. Here we describe a mechanism whereby proteins containing a pentapeptide sequence, biochemically related to the KFERQ-motif, are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, this mechanism is independent of the ESCRT machinery components TSG101 and VPS4b and dependent on HSC70, CD63, Alix, Syntenin-1, Rab31 and ceramides. The transcription factor and master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. Additionally, by tagging fluorescent proteins with KFERQ-like sequences we were able to follow inter-organ transfer of exosomes in zebrafish larvae. Our findings identify LAMP2A as a key component in exosome biogenesis while opening new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.

Competing Interest Statement

(Instituto de Biologia Experimental e Tecnologica) IBET Patent: A method for selective loading of proteins into exosomes and products thereof, PCT/IB2020/051341, by inventors Joao Vasco Ferreira, Ana da Rosa Soares and Paulo Pereira.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 26, 2021.
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LAMP2A regulates the loading of proteins into exosomes
João Vasco Ferreira, Ana da Rosa Soares, José Ramalho, Catarina Máximo Carvalho, Maria Helena Cardoso, Petra Pintado, Ana Sofia Carvalho, Hans Christian Beck, Rune Matthiesen, Mónica Zuzarte, Henrique Girão, Guillaume van Niel, Paulo Pereira
bioRxiv 2021.07.26.453637; doi: https://doi.org/10.1101/2021.07.26.453637
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LAMP2A regulates the loading of proteins into exosomes
João Vasco Ferreira, Ana da Rosa Soares, José Ramalho, Catarina Máximo Carvalho, Maria Helena Cardoso, Petra Pintado, Ana Sofia Carvalho, Hans Christian Beck, Rune Matthiesen, Mónica Zuzarte, Henrique Girão, Guillaume van Niel, Paulo Pereira
bioRxiv 2021.07.26.453637; doi: https://doi.org/10.1101/2021.07.26.453637

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