Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease
Celiac disease (CD) represents a frequent autoimmune disease triggered by the ingestion of gliadin in genetically predisposed individuals. The alteration of enterocytes and brush border membrane morphology have been repetitively demonstrated, but the underlying mechanisms remain unclear. Microtubule...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/3/2635 |
| _version_ | 1797624357305974784 |
|---|---|
| author | Sebastian Stricker Manuel Müller Klaus-Peter Zimmer Ralf Jacob |
| author_facet | Sebastian Stricker Manuel Müller Klaus-Peter Zimmer Ralf Jacob |
| author_sort | Sebastian Stricker |
| collection | DOAJ |
| description | Celiac disease (CD) represents a frequent autoimmune disease triggered by the ingestion of gliadin in genetically predisposed individuals. The alteration of enterocytes and brush border membrane morphology have been repetitively demonstrated, but the underlying mechanisms remain unclear. Microtubules represent a major element of the cytoskeleton and exert multiple functions depending on their tyrosination status. The aim of our study was to investigate whether posttranslational modification of microtubules was altered in the context of CD and whether this mechanism contributed to morphological changes of CD enterocytes. We examined the expression of tubulin tyrosine ligase (TTL) and vasohibin-2 (VASH2) and the level of detyrosinated and acetylated tubulin in duodenal biopsies and Caco-2 cells by immunoblot and immunofluorescence microcopy. Electron microscopy was performed to investigate the subcellular distribution of detyrosinated tubulin and brush border membrane architecture in CD biopsies and Madin–Darby Canine Kidney type II (MDCK) cells lacking TTL. CD enterocytes and Caco-2 cells stimulated with digested gliadin or IFN-y displayed a flattened cell morphology. This disturbed cellular architecture was accompanied by an increased amount of detyrosinated and acetylated tubulin and corresponding high expression of VASH2 and low expression of TTL. The altered posttranslational modification of tubulin was reversible after the introduction of the gluten-free diet. CD enterocytes and MDCK cells deficient in TTL displayed a reduced cell height along with an increased cell width and a reduced number of apical microvilli. Our results provide a functional explanation for the observed morphological alterations of the enterocytes observed in CD and provide diagnostic potential of the tyrosination status of microtubules as an early marker of villous atrophy and CD inflammation. |
| first_indexed | 2024-03-11T09:41:14Z |
| format | Article |
| id | doaj.art-ce9cd822800a4d7f8cc5c8da9ce7f227 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:41:14Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ce9cd822800a4d7f8cc5c8da9ce7f2272023-11-16T17:00:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243263510.3390/ijms24032635Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac DiseaseSebastian Stricker0Manuel Müller1Klaus-Peter Zimmer2Ralf Jacob3Department of Pediatrics, Justus-Liebig-University Giessen, 35392 Giessen, GermanyDepartment of Cell Biology and Cell Pathology, Philipps-University Marburg, 35032 Marburg, GermanyDepartment of Pediatrics, Justus-Liebig-University Giessen, 35392 Giessen, GermanyDepartment of Cell Biology and Cell Pathology, Philipps-University Marburg, 35032 Marburg, GermanyCeliac disease (CD) represents a frequent autoimmune disease triggered by the ingestion of gliadin in genetically predisposed individuals. The alteration of enterocytes and brush border membrane morphology have been repetitively demonstrated, but the underlying mechanisms remain unclear. Microtubules represent a major element of the cytoskeleton and exert multiple functions depending on their tyrosination status. The aim of our study was to investigate whether posttranslational modification of microtubules was altered in the context of CD and whether this mechanism contributed to morphological changes of CD enterocytes. We examined the expression of tubulin tyrosine ligase (TTL) and vasohibin-2 (VASH2) and the level of detyrosinated and acetylated tubulin in duodenal biopsies and Caco-2 cells by immunoblot and immunofluorescence microcopy. Electron microscopy was performed to investigate the subcellular distribution of detyrosinated tubulin and brush border membrane architecture in CD biopsies and Madin–Darby Canine Kidney type II (MDCK) cells lacking TTL. CD enterocytes and Caco-2 cells stimulated with digested gliadin or IFN-y displayed a flattened cell morphology. This disturbed cellular architecture was accompanied by an increased amount of detyrosinated and acetylated tubulin and corresponding high expression of VASH2 and low expression of TTL. The altered posttranslational modification of tubulin was reversible after the introduction of the gluten-free diet. CD enterocytes and MDCK cells deficient in TTL displayed a reduced cell height along with an increased cell width and a reduced number of apical microvilli. Our results provide a functional explanation for the observed morphological alterations of the enterocytes observed in CD and provide diagnostic potential of the tyrosination status of microtubules as an early marker of villous atrophy and CD inflammation.https://www.mdpi.com/1422-0067/24/3/2635celiac diseasemicrotubulesdetyrosinated tubulintubulin tyrosine ligasevasohibin-2 |
| spellingShingle | Sebastian Stricker Manuel Müller Klaus-Peter Zimmer Ralf Jacob Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease International Journal of Molecular Sciences celiac disease microtubules detyrosinated tubulin tubulin tyrosine ligase vasohibin-2 |
| title | Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease |
| title_full | Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease |
| title_fullStr | Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease |
| title_full_unstemmed | Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease |
| title_short | Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease |
| title_sort | altered posttranslational modification of microtubules contributes to disturbed enterocyte morphology in celiac disease |
| topic | celiac disease microtubules detyrosinated tubulin tubulin tyrosine ligase vasohibin-2 |
| url | https://www.mdpi.com/1422-0067/24/3/2635 |
| work_keys_str_mv | AT sebastianstricker alteredposttranslationalmodificationofmicrotubulescontributestodisturbedenterocytemorphologyinceliacdisease AT manuelmuller alteredposttranslationalmodificationofmicrotubulescontributestodisturbedenterocytemorphologyinceliacdisease AT klauspeterzimmer alteredposttranslationalmodificationofmicrotubulescontributestodisturbedenterocytemorphologyinceliacdisease AT ralfjacob alteredposttranslationalmodificationofmicrotubulescontributestodisturbedenterocytemorphologyinceliacdisease |