Detection of 3-nitrotyrosine-modified human leukocyte antigen–G in biological fluids

Díaz‐Lagares, Ángel; Alegre, Estíbaliz; González, Álvaro

doi:10.1016/j.humimm.2009.07.018

Cited by 14 publications

(6 citation statements)

References 40 publications

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“…In addition to the different isoforms, the structure of HLA-G is even more complex, since these isoforms can be presented as homo- and hetero-multimers resulting from intermolecular disulphide bonds by Cys 42 or Cys 147 in the α1 or α2 domain, respectively. Furthermore, HLA-G molecules can be ubiquitinated, glycosylated and nitrated by post-translational modifications ( 21 – 23 ). Finally, HLA-G has been reported as a part of exosomes ( 24 ).…”

Section: Diversity Of the Hla-g Isoformsmentioning

confidence: 99%

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

2018

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Phenotypic heterogeneity has been observed in most malignancies, which represents a considerable challenge for tumor therapy. In recent decades, the biological function and clinical significance of the human leukocyte antigen (HLA)-G have been intensively explored. It is now widely accepted that HLA-G is a critical marker of immunotolerance in cancer cell immune evasion and is strongly associated with disease progress and prognosis for cancer patients. Moreover, it has recently been emphasized that the signaling pathway linking HLA-G and immunoglobulin-like transcripts (ILTs) is considered an immune checkpoint. In addition, HLA-G itself can generate at least seven distinct isoforms, and intertumor and intratumor heterogeneity of HLA-G expression is common across different tumor types. Furthermore, HLA-G heterogeneity in cancers has been related to disease stage and outcomes, metastatic status and response to different therapies. This review focuses on the heterogeneity of HLA-G expression in malignant lesions, and clinical implications of this heterogeneity that might be relevant to personalized treatments are also discussed.

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Section: Diversity Of the Hla-g Isoformsmentioning

confidence: 99%

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

2018

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“…Another posttranslational modification observed in HLA-G is nitration in Tyr residues. Presence of 3-nitrotryrosine in HLA-G has been demonstrated in vivo in biological fluids both in monomeric and multimeric form [42] and in vitro after treatment with NO donors, which also increase HLA-G shedding by metalloproteases [43]. The detection of this modified HLA-G may characterize HLA-G synthesized at sites of inflammation where there is an important peroxide production.…”

Section: Posttranslational Modifications Of Hla-g Moleculementioning

confidence: 99%

“…Probably the most important issue is related to the types of HLA-G molecules present in biological fluids, as we do not know yet the predominant isoform and whether it circulates free or included in microvesicles, that is, exosomes [64], or if they are mainly free molecules or associated with β 2-m, or even the influence of modifications such as dimerization [92], nitration [42], or ubiquitination [97]. The presence of these altered structures could be more relevant in cancer where there is a deeply altered microenvironment.…”

Section: Analytical Challenging In Soluble Hla-g Analysismentioning

confidence: 99%

Some Basic Aspects of HLA-G Biology

Alegre

Rizzo

Bortolotti

et al. 2014

Journal of Immunology Research

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Human leukocyte antigen-G (HLA-G) is a low polymorphic nonclassical HLA-I molecule restrictively expressed and with suppressive functions. HLA-G gene products are quite complex, with seven HLA-G isoforms, four membrane bound, and other three soluble isoforms that can suffer different posttranslational modifications or even complex formations. In addition, HLA-G has been described included in exosomes. In this review we will focus on HLA-G biochemistry with special emphasis to the mechanisms that regulate its expression and how the protein modifications affect the quantification in biological fluids.

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“…Three types of posttranslational modifications have been described in HLA-G protein: (i) N-glycosylation in the residue Asn86 [9], (ii) nitration by NO [10], and (iii) intermolecular disulphide bonds giving rise to multimeric forms [11]. These multimeric structures of HLA-G have been previously observed using electrophoresis under nonreducing conditions in different exudates [12]. HLA-G1 can also be shed from cellular membranes (sHLA-G1) into the medium via metalloprotease activity [10,13].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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 antiubiquitin 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.Keywords: Exosome r Exudates r HLA-G r Molecular immunology r Ubiquitin Additional supporting information may be found in the online version of this article at the publisher's web-site

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Detection of 3-nitrotyrosine-modified human leukocyte antigen–G in biological fluids

Cited by 14 publications

References 40 publications

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

Some Basic Aspects of HLA-G Biology

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

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