4.5 Article

In vivo identification of an HLA-G complex as ubiquitinated protein circulating in exosomes

Journal

EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 43, Issue 7, Pages 1933-1939

Publisher

WILEY-BLACKWELL
DOI: 10.1002/eji.201343318

Keywords

Exosome; Exudates; HLA-G; Molecular immunology; Ubiquitin

Categories

Funding

  1. Plan de Investigacion de la Universidad de Navarra
  2. Fondo de Investigacion Sanitaria [PI11/02119]
  3. Xunta de Galicia and European Social Fund.

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The nonclassical human leukocyte antigen-G (HLA-G) is a tolerogenic molecule that can be released to the circulation by expressing cells. This molecule can form dimers but some other complexed HLA-G forms have been proposed to be present in vivo. Here, we further characterized these other complexed HLA-G forms in vivo. Ascitic and pleural exudates from patients were selected based on positivity for HLA-G by ELISA. Complexed HLA-G was detected in exosomes, which indicates an intracellular origin of these forms. 2D-PAGE analysis of exudates and isolated exosomes showed that these high molecular weight complexes were more heterogeneous than the HLA-G1 expressed by cell cultures. Treatment with deglycosylating enzymes did not change the molecular weight of HLA-G complexes. Immunoblot analysis of exudates and exosomes with an anti-ubiquitin antibody showed that at least some of these structures correspond to ubiquitinated HLA-G. HLA-G ubiquitination could be reproduced in vitro in HLA-G1-transfected cell lines, although with a lower modified/nonmodified protein proportion than in exudates. In summary, we demonstrate new circulating HLA-G forms in vivo that open a new perspective in the study of HLA-G function and analysis.

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