LAMP2A regulates the loading of proteins into exosomes

Author:

Ferreira João Vasco1ORCID,da Rosa Soares Ana1ORCID,Ramalho José1ORCID,Máximo Carvalho Catarina1ORCID,Cardoso Maria Helena1ORCID,Pintado Petra2ORCID,Carvalho Ana Sofia3ORCID,Beck Hans Christian4,Matthiesen Rune3ORCID,Zuzarte Mónica5ORCID,Girão Henrique5,van Niel Guillaume67ORCID,Pereira Paulo1ORCID

Affiliation:

1. Proteostasis and Proteolytic Signalling Lab, Chronic Diseases Research Centre (CEDOC), NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal.

2. Fish Facility, CEDOC, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal.

3. Computational and Experimental Biology Group, CEDOC, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Lisbon, Portugal.

4. Centre for Clinical Proteomics, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.

5. University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Center for Innovative Biomedicine and Biotechnology (CIBB), Clinical Academic Centre of Coimbra (CACC), Coimbra, Portugal.

6. Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, F-75014 Paris, France.

7. GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014 Paris, France.

Abstract

Exosomes are extracellular vesicles of endosomal origin that are released by practically 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. Here, we describe a mechanism whereby proteins containing a KFERQ motif pentapeptide are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, we demonstrate that this mechanism is independent of the ESCRT machinery but dependent on HSC70, CD63, Alix, Syntenin-1, Rab31, and ceramides. We show that the master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. In addition, by tagging fluorescent proteins with KFERQ-like sequences, we were able to follow the interorgan transfer of exosomes. Our findings open new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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