Cargando…

Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation

Post-translational modifications can lead to a break in immune tolerance in autoimmune diseases such as type 1 diabetes (T1D). Deamidation, the conversion of glutamine to glutamic acid by transglutaminase (TGM) enzymes, is a post-translational modification of interest, with deamidated peptides being...

Descripción completa

Detalles Bibliográficos
Autores principales: Callebaut, Aїsha, Bruggeman, Ylke, Zamit, Cloé, Sodré, Fernanda Marques Câmara, Irla, Magali, Mathieu, Chantal, Buitinga, Mijke, Overbergh, Lut
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367685/
https://www.ncbi.nlm.nih.gov/pubmed/35966081
http://dx.doi.org/10.3389/fendo.2022.908248
_version_ 1784765882290929664
author Callebaut, Aїsha
Bruggeman, Ylke
Zamit, Cloé
Sodré, Fernanda Marques Câmara
Irla, Magali
Mathieu, Chantal
Buitinga, Mijke
Overbergh, Lut
author_facet Callebaut, Aїsha
Bruggeman, Ylke
Zamit, Cloé
Sodré, Fernanda Marques Câmara
Irla, Magali
Mathieu, Chantal
Buitinga, Mijke
Overbergh, Lut
author_sort Callebaut, Aїsha
collection PubMed
description Post-translational modifications can lead to a break in immune tolerance in autoimmune diseases such as type 1 diabetes (T1D). Deamidation, the conversion of glutamine to glutamic acid by transglutaminase (TGM) enzymes, is a post-translational modification of interest, with deamidated peptides being reported as autoantigens in T1D. However, little is known about how Tgm2, the most ubiquitously expressed Tgm isoform, is regulated and how tolerance against deamidated peptides is lost. Here, we report on the aberrant expression and regulation of Tgm2 in the pancreas and thymus of NOD mice. We demonstrate that Tgm2 expression is induced by the inflammatory cytokines IL1β and IFNγ in a synergistic manner and that murine pancreatic islets of NOD mice have higher Tgm2 levels, while Tgm2 levels in medullary thymic epithelial cells are reduced. We thus provide the first direct evidence to our knowledge that central tolerance establishment against deamidated peptides might be impaired due to lower Tgm2 expression in NOD medullary thymic epithelial cells, which together with the aberrantly high levels of deamidated peptides in NOD β-cells underscores the role of deamidation in amplifying T-cell reactivity.
format Online
Article
Text
id pubmed-9367685
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-93676852022-08-12 Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation Callebaut, Aїsha Bruggeman, Ylke Zamit, Cloé Sodré, Fernanda Marques Câmara Irla, Magali Mathieu, Chantal Buitinga, Mijke Overbergh, Lut Front Endocrinol (Lausanne) Endocrinology Post-translational modifications can lead to a break in immune tolerance in autoimmune diseases such as type 1 diabetes (T1D). Deamidation, the conversion of glutamine to glutamic acid by transglutaminase (TGM) enzymes, is a post-translational modification of interest, with deamidated peptides being reported as autoantigens in T1D. However, little is known about how Tgm2, the most ubiquitously expressed Tgm isoform, is regulated and how tolerance against deamidated peptides is lost. Here, we report on the aberrant expression and regulation of Tgm2 in the pancreas and thymus of NOD mice. We demonstrate that Tgm2 expression is induced by the inflammatory cytokines IL1β and IFNγ in a synergistic manner and that murine pancreatic islets of NOD mice have higher Tgm2 levels, while Tgm2 levels in medullary thymic epithelial cells are reduced. We thus provide the first direct evidence to our knowledge that central tolerance establishment against deamidated peptides might be impaired due to lower Tgm2 expression in NOD medullary thymic epithelial cells, which together with the aberrantly high levels of deamidated peptides in NOD β-cells underscores the role of deamidation in amplifying T-cell reactivity. Frontiers Media S.A. 2022-07-26 /pmc/articles/PMC9367685/ /pubmed/35966081 http://dx.doi.org/10.3389/fendo.2022.908248 Text en Copyright © 2022 Callebaut, Bruggeman, Zamit, Sodré, Irla, Mathieu, Buitinga and Overbergh https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Callebaut, Aїsha
Bruggeman, Ylke
Zamit, Cloé
Sodré, Fernanda Marques Câmara
Irla, Magali
Mathieu, Chantal
Buitinga, Mijke
Overbergh, Lut
Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation
title Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation
title_full Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation
title_fullStr Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation
title_full_unstemmed Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation
title_short Aberrant expression of transglutaminase 2 in pancreas and thymus of NOD mice underscores the importance of deamidation in neoantigen generation
title_sort aberrant expression of transglutaminase 2 in pancreas and thymus of nod mice underscores the importance of deamidation in neoantigen generation
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367685/
https://www.ncbi.nlm.nih.gov/pubmed/35966081
http://dx.doi.org/10.3389/fendo.2022.908248
work_keys_str_mv AT callebautaísha aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT bruggemanylke aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT zamitcloe aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT sodrefernandamarquescamara aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT irlamagali aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT mathieuchantal aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT buitingamijke aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration
AT overberghlut aberrantexpressionoftransglutaminase2inpancreasandthymusofnodmiceunderscorestheimportanceofdeamidationinneoantigengeneration