{rfName}
IS

Indexed in

License and use

Icono OpenAccess

Citations

1352

Altmetrics

Grant support

We thank Dr K. Knobeloch, Dr A. Garcia-Sastre and Dr M.A. Alonso for providing reagents, and Dr S. Bartlett for assistance with English editing. C.E. is thankful to electron microscopy facility (campus Casanova), CCiT-University of Barcelona. This study was supported by grants SAF2014-55579-R from the Spanish Ministry of Economy and Competitiveness, INDISNET-S2011/BMD-2332 from the Comunidad de Madrid, Cardiovascular Network RD12-0042-0056 and PIE13/00041 from Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER), ERC-2011-AdG 294340-GENTRIS and COST-Action BM1202 to F.S.-M.; grant SAF2014-54623-R, FIS grant PI11/00127 (Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III and Ministry of Health of Spain, State secretary of R+D and FEDER/FSE) and Bayer Group Grants4Grants (ID 2013-08-0982) to S.G.; and grant BFU2015-66785-P from the Spanish Ministry of Economy and Competitiveness to C.E.; Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). C.V.-B. was supported by FPU programme (Spanish Ministry of Education). M. M. is supported by MS14/00219 from Instituto de Salud Carlos III.

Analysis of institutional authors

Villarroya-Beltri, CarolinaAuthorMittelbrunn, MariaAuthorFernandez-Delgado, IreneAuthorTorralba, DanielAuthorMoreno-Gonzalo, OlgaAuthorBaldanta, SaraAuthorGuerra, SusanaAuthorSanchez-Madrid, FranciscoAuthor

Share

Publications
>
Article

ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins

Publicated to:Nature Communications. 7 (13588): 13588- - 2016-11-24 7(13588), DOI: 10.1038/ncomms13588

Authors: Villarroya-Beltri, Carolina; Baixauli, Francesc; Mittelbrunn, Maria; Fernandez-Delgado, Irene; Torralba, Daniel; Moreno-Gonzalo, Olga; Baldanta, Sara; Enrich, Carlos; Guerra, Susana; Sanchez-Madrid, Francisco

Affiliations

Abstract

Exosomes are vesicles secreted to the extracellular environment through fusion with the plasma membrane of specific endosomes called multivesicular bodies (MVB) and mediate cell-to-cell communication in many biological processes. Posttranslational modifications are involved in the sorting of specific proteins into exosomes. Here we identify ISGylation as a ubiquitin-like modification that controls exosome release. ISGylation induction decreases MVB numbers and impairs exosome secretion. Using ISG15-knockout mice and mice expressing the enzymatically inactive form of the de-ISGylase USP18, we demonstrate in vitro and in vivo that ISG15 conjugation regulates exosome secretion. ISG15 conjugation triggers MVB co-localization with lysosomes and promotes the aggregation and degradation of MVB proteins. Accordingly, inhibition of lysosomal function or autophagy restores exosome secretion. Specifically, ISGylation of the MVB protein TSG101 induces its aggregation and degradation, being sufficient to impair exosome secretion. These results identify ISGylation as a novel ubiquitin-like modifier in the control of exosome production.

Keywords

Autophagic vacuolesHuman-cellsInterferon-stimulated geneIsg15 conjugationLigase activityMembrane-proteinsMultivesicular body formationPlasma-membraneUbiquitin-like proteinViral resistance

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Communications due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2016, it was in position 3/63, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 7.61. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 11.2 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 37.76 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-06, the following number of citations:

  • WoS: 287
  • Scopus: 372
  • Europe PMC: 220
  • Google Scholar: 473
  • OpenCitations: 362

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-06:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 495.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 495 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 66.5.
  • The number of mentions on the social network Facebook: 2 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 4 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (VILLARROYA BELTRI, CAROLINA) and Last Author (SANCHEZ MADRID, FRANCISCO).