LAMP2A regulates the loading of proteins into exosomes

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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.

Abstract

LAMP2A targets cytosolic proteins to extracellular vesicles to modulate interorgan communication.

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Most cited references 57

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Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Yoav Benjamini, Yosef Hochberg (1995)

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Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Clotilde Théry, Kenneth W Witwer, Elena Aikawa … (2019)

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

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MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.

Jürgen Cox, Matthias Mann (2008)

Efficient analysis of very large amounts of raw data for peptide identification and protein quantification is a principal challenge in mass spectrometry (MS)-based proteomics. Here we describe MaxQuant, an integrated suite of algorithms specifically developed for high-resolution, quantitative MS data. Using correlation analysis and graph theory, MaxQuant detects peaks, isotope clusters and stable amino acid isotope-labeled (SILAC) peptide pairs as three-dimensional objects in m/z, elution time and signal intensity space. By integrating multiple mass measurements and correcting for linear and nonlinear mass offsets, we achieve mass accuracy in the p.p.b. range, a sixfold increase over standard techniques. We increase the proportion of identified fragmentation spectra to 73% for SILAC peptide pairs via unambiguous assignment of isotope and missed-cleavage state and individual mass precision. MaxQuant automatically quantifies several hundred thousand peptides per SILAC-proteome experiment and allows statistically robust identification and quantification of >4,000 proteins in mammalian cell lysates.

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Author and article information

Contributors

João Vasco Ferreira:

ORCID: https://orcid.org/0000-0001-5897-7461

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Ana da Rosa Soares:

ORCID: https://orcid.org/0000-0002-0371-4610

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

José Ramalho:

ORCID: https://orcid.org/0000-0002-1927-164X

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Resources

Catarina Máximo Carvalho:

ORCID: https://orcid.org/0000-0002-9842-3479

Role: Data curationRole: Formal analysisRole: InvestigationRole: Validation

Maria Helena Cardoso:

ORCID: https://orcid.org/0000-0002-3634-1128

Role: Data curationRole: InvestigationRole: Validation

Petra Pintado:

ORCID: https://orcid.org/0000-0003-3635-6220

Role: InvestigationRole: Methodology

Ana Sofia Carvalho:

ORCID: https://orcid.org/0000-0003-0657-1907

Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Hans Christian Beck: Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - review & editing

Rune Matthiesen:

ORCID: https://orcid.org/0000-0002-6353-2616

Role: Formal analysisRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Mónica Zuzarte:

ORCID: https://orcid.org/0000-0001-8294-6980

Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - review & editing

Henrique Girão: Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Writing - original draftRole: Writing - review & editing

Guillaume van Niel:

ORCID: https://orcid.org/0000-0002-8651-9705

Role: ConceptualizationRole: InvestigationRole: Writing - review & editing

Paulo Pereira:

ORCID: https://orcid.org/0000-0002-9908-2290

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: March 2022

Publication date (Electronic, pub): 25 March 2022

Volume: 8

Issue: 12

Electronic Location Identifier: eabm1140

Affiliations

[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.

Author notes

[* ]Corresponding author. Email: paulo.pereira@ 123456nms.unl.pt

[†]

These authors contributed equally to this work.

Author information

João Vasco Ferreira https://orcid.org/0000-0001-5897-7461

Ana da Rosa Soares https://orcid.org/0000-0002-0371-4610

José Ramalho https://orcid.org/0000-0002-1927-164X

Catarina Máximo Carvalho https://orcid.org/0000-0002-9842-3479

Maria Helena Cardoso https://orcid.org/0000-0002-3634-1128

Petra Pintado https://orcid.org/0000-0003-3635-6220

Ana Sofia Carvalho https://orcid.org/0000-0003-0657-1907

Rune Matthiesen https://orcid.org/0000-0002-6353-2616

Mónica Zuzarte https://orcid.org/0000-0001-8294-6980

Guillaume van Niel https://orcid.org/0000-0002-8651-9705

Paulo Pereira https://orcid.org/0000-0002-9908-2290

Article

Publisher ID: abm1140

DOI: 10.1126/sciadv.abm1140

PMC ID: 8956266

PubMed ID: 35333565

SO-VID: 8954156d-6901-4a2f-9a5b-f4fa614a00e8

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 26 August 2021

Date accepted : 04 February 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;

Award ID: SFRH/BPD/121271/2016

Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;

Award ID: PD/BD/106052/2015

Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;

Award ID: PD/BD/136902/2018

Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;

Award ID: PTDC/SAU-ORG/118694/2010

Funded by: iNOVA4Health;

Award ID: LISBOA-01-0145-FEDER-007344

Funded by: FEDER/ Project;

Award ID: 02/SAICT/2020/072552

Funded by: FundRef http://dx.doi.org/10.13039/501100008530, European Regional Development Fund;

Award ID: NOVA4H

Funded by: UIDB Multi;

Award ID: 04462/2020

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LAMP2A regulates the loading of proteins into exosomes

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Most cited references 57

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.

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Cited by 47

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