{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T05:08:48Z","timestamp":1778389728068,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Celiac disease (CD) is an autoimmune inflammatory enteropathy triggered by consuming gluten-containing cereals. A key role in its pathogenesis is played by type 2 transglutaminase, an enzyme that causes an increase in gluten immunogenicity. Celiac cells seem to present constitutive characteristics, even recognizable under a gluten-free diet, such as defects in vesicular trafficking and autophagy, protein hyperphosphorylation, and cytoskeleton rearrangement. In this work, by using an omics approach, we attempted to identify those proteins differentially expressed or differentially phosphorylated in a cell model suitable to study cell behavior in the absence of inflammation, i.e., primary cultures of dermal fibroblasts from control or CD subjects. By performing mass spectrometry analyses, we found several up- and-down expressed or phosphorylated proteins in CD samples, mainly involved in signaling, homeostatic responses, cytoskeleton organization, vesicular trafficking, and extracellular vesiculation. These proteins may represent a molecular signature of the celiac cellular phenotype and may contribute to adding new insight into the comprehension of the complex mechanisms of CD pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms27093938","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:09:33Z","timestamp":1777388973000},"page":"3938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteomic Analysis Highlights Peculiar Protein and Phosphoprotein Profiles in Dermal Fibroblasts from Celiac Disease Patients"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5553-2137","authenticated-orcid":false,"given":"Antonio","family":"Montefusco","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Laura","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Massimiliano","family":"Romanelli","sequence":"additional","affiliation":[{"name":"Department of Engineering, University of Sannio, 82100 Benevento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2569-4606","authenticated-orcid":false,"given":"Merlin","family":"Nanayakkara","sequence":"additional","affiliation":[{"name":"Federico II University Hospital, 80131 Naples, Italy"},{"name":"European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University Federico II, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-4917","authenticated-orcid":false,"given":"Maria Vittoria","family":"Barone","sequence":"additional","affiliation":[{"name":"European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University Federico II, 80131 Naples, Italy"},{"name":"Department of Translational Medical Science, University Federico II, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8643-5018","authenticated-orcid":false,"given":"Fabrizio","family":"Dal Piaz","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2825-9711","authenticated-orcid":false,"given":"Ivana","family":"Caputo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, University Federico II, 80131 Naples, Italy"},{"name":"Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-3829","authenticated-orcid":false,"given":"Gaetana","family":"Paolella","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1146\/annurev.immunol.18.1.53","article-title":"Molecular Basis of Celiac Disease","volume":"18","author":"Sollid","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/MCG.0000000000001267","article-title":"Celiac Disease: Extraintestinal Manifestations and Associated Conditions","volume":"54","author":"Therrien","year":"2020","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s42003-019-0443-1","article-title":"Constitutive Alterations in Vesicular Trafficking Increase the Sensitivity of Cells from Celiac Disease Patients to Gliadin","volume":"2","author":"Lania","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nanayakkara, M., Lania, G., Maglio, M., Kosova, R., Sarno, M., Gaito, A., Discepolo, V., Troncone, R., Auricchio, S., and Auricchio, R. (2013). Enterocyte Proliferation and Signaling Are Constitutively Altered in Celiac Disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076006"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Paolella, G., Nanayakkara, M., Sposito, S., Lepretti, M., Auricchio, S., Esposito, C., Barone, M.V., Martucciello, S., and Caputo, I. (2020). Constitutive Differential Features of Type 2 Transglutaminase in Cells Derived from Celiac Patients and from Healthy Subjects. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041231"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sposito, S., Secondo, A., Romanelli, A.M., Montefusco, A., Nanayakkara, M., Auricchio, S., Barone, M.V., Caputo, I., and Paolella, G. (2023). Peculiar Ca2+ Homeostasis, ER Stress, Autophagy, and TG2 Modulation in Celiac Disease Patient-Derived Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021495"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nanayakkara, M., Kosova, R., Lania, G., Sarno, M., Gaito, A., Galatola, M., Greco, L., Cuomo, M., Troncone, R., and Auricchio, S. (2013). A Celiac Cellular Phenotype, with Altered LPP Sub-Cellular Distribution, Is Inducible in Controls by the Toxic Gliadin Peptide P31-43. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079763"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00726-016-2307-z","article-title":"Celiac Anti-Type 2 Transglutaminase Antibodies Induce Differential Effects in Fibroblasts from Celiac Disease Patients and from Healthy Subjects","volume":"49","author":"Paolella","year":"2017","journal-title":"Amino Acids"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2100057","DOI":"10.1002\/pmic.202100057","article-title":"Insights from Tissue \u201cOmics\u201d Analysis on Intestinal Remodeling in Celiac Disease","volume":"21","author":"Stamnaes","year":"2021","journal-title":"Proteomics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/j.ajpath.2018.03.017","article-title":"Characterization of the Small Intestinal Lesion in Celiac Disease by Label-Free Quantitative Mass Spectrometry","volume":"188","author":"Tutturen","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1053\/j.gastro.2024.03.006","article-title":"Biopsy Proteome Scoring to Determine Mucosal Remodeling in Celiac Disease","volume":"167","author":"Johansen","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29872","DOI":"10.1038\/s41598-024-80391-5","article-title":"Proteomic Analysis of Plasma and Duodenal Tissue in Celiac Disease Patients Reveals Potential Noninvasive Diagnostic Biomarkers","volume":"14","author":"Li","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100803","DOI":"10.1016\/j.gastha.2025.100803","article-title":"Plasma Proteins Invariant to Diet in Celiac Disease: Results from a Proteomics Study on the UK Biobank","volume":"5","author":"Hujoel","year":"2025","journal-title":"Gastro Hep Adv."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yang, Q., Langston, J.C., Tang, Y., Kiani, M.F., and Kilpatrick, L.E. (2019). The Role of Tyrosine Phosphorylation of Protein Kinase C Delta in Infection and Inflammation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061498"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10798","DOI":"10.1038\/s41598-020-67889-4","article-title":"mTOR Sustains Inflammatory Response in Celiac Disease","volume":"10","author":"Sedda","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105412","DOI":"10.1016\/j.phrs.2020.105412","article-title":"Posttranslational Modifications as Therapeutic Targets for Intestinal Disorders","volume":"165","author":"Choo","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9495","DOI":"10.1111\/jcmm.15608","article-title":"Sepiapterin Reductase: Characteristics and Role in Diseases","volume":"24","author":"Wu","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10430","DOI":"10.12998\/wjcc.v9.i34.10430","article-title":"Association between Celiac Disease and Vitiligo: A Review of the Literature","volume":"9","author":"Zhang","year":"2021","journal-title":"WJCC"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, Y., Ande, S.R., and Mishra, S. (2012). Phosphorylation of Transglutaminase 2 (TG2) at Serine-216 Has a Role in TG2 Mediated Activation of Nuclear Factor-Kappa B and in the Downregulation of PTEN. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-277"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Uehara, R., Yamada, E., Okada, S., Bastie, C.C., Maeshima, A., Ikeuchi, H., Horiguchi, K., and Yamada, M. (2023). Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and P53 Expression in the Development of Diabetic Kidney Disease. Cells, 12.","DOI":"10.3390\/cells12081197"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Efthymakis, K., Bologna, G., Simeone, P., Pierdomenico, L., Catitti, G., Vespa, S., Milano, A., Bellis, D.D., Laterza, F., and Pandolfi, A. (2022). Circulating Extracellular Vesicles Are Increased in Newly Diagnosed Celiac Disease Patients. Nutrients, 15.","DOI":"10.3390\/nu15010071"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C846","DOI":"10.1152\/ajpcell.00290.2021","article-title":"Role of Glypican-1 in Regulating Multiple Cellular Signaling Pathways","volume":"321","author":"Pan","year":"2021","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nature14581","article-title":"Glypican-1 Identifies Cancer Exosomes and Detects Early Pancreatic Cancer","volume":"523","author":"Melo","year":"2015","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1247\/csf.20012","article-title":"MON2 Guides Wntless Transport to the Golgi through Recycling Endosomes","volume":"45","author":"Zhao","year":"2020","journal-title":"Cell Struct. Funct."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5618","DOI":"10.1007\/s12035-021-02504-9","article-title":"The Golgi-Associated PDZ Domain Protein Gopc\/PIST Is Required for Synaptic Targeting of mGluR5","volume":"58","author":"Song","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1042\/BJ20060897","article-title":"CHMP7, a Novel ESCRT-III-Related Protein, Associates with CHMP4b and Functions in the Endosomal Sorting Pathway","volume":"400","author":"Horii","year":"2006","journal-title":"Biochem. J."},{"key":"ref_27","first-page":"2781","article-title":"\u03b3-SNAP Stimulates Disassembly of Endosomal SNARE Complexes and Regulates Endocytic Trafficking Pathways","volume":"128","author":"Inoue","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R968","DOI":"10.1016\/j.cub.2004.10.045","article-title":"Membrane Traffic: Controlling Membrane Fusion by Modifying NSF","volume":"14","author":"Morgan","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1087-0024.2005.200402.x","article-title":"CLIC4, an Intracellular Chloride Channel Protein, Is a Novel Molecular Target for Cancer Therapy","volume":"10","author":"Suh","year":"2005","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13062-025-00644-9","article-title":"Gliadin-Dependent UPR Induction Directly Triggers the Expression of TG2 and pro-Inflammatory Cytokines, Dysregulates Intestinal Permeability, and Reduces CFTR Expression in Intestinal Epithelial Cells of Celiac Disease Patients","volume":"20","author":"Monzani","year":"2025","journal-title":"Biol. Direct"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Discepolo, V., Lania, G., Ten Eikelder, M.L.G., Nanayakkara, M., Sepe, L., Tufano, R., Troncone, R., Auricchio, S., Auricchio, R., and Paolella, G. (2021). Pediatric Celiac Disease Patients Show Alterations of Dendritic Cell Shape and Actin Rearrangement. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052708"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, J., Zhang, Y., Li, Q., and Wang, Y. (2020). Transgelins: Cytoskeletal Associated Proteins Implicated in the Metastasis of Colorectal Cancer. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.573859"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Xiong, Y., Wang, C., Shi, L., Wang, L., Zhou, Z., Chen, D., Wang, J., and Guo, H. (2017). Myosin Light Chain Kinase: A Potential Target for Treatment of Inflammatory Diseases. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00292"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/(SICI)1097-4644(19960601)61:3<363::AID-JCB4>3.0.CO;2-R","article-title":"Conversion of Dermal Fibroblasts to a Myogenic Lineage Is Induced by a Soluble Factor Derived from Myoblasts","volume":"61","author":"Wise","year":"1996","journal-title":"J. Cell Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1159\/000049507","article-title":"Increased Levels of IgA Antibodies against Desmin in Children with Coeliac Disease","volume":"126","author":"Teesalu","year":"2001","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"102847","DOI":"10.1016\/j.jbc.2022.102847","article-title":"Phosphorylation Alters the Mechanical Stiffness of a Model Fragment of the Dystrophin Homologue Utrophin","volume":"299","author":"Ramirez","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.2174\/1871520621666210119093327","article-title":"\u03b3-Synuclein Is Closely Involved in Autophagy that Protects Colon Cancer Cell from Endoplasmic Reticulum Stress","volume":"21","author":"Ye","year":"2021","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.chom.2009.09.006","article-title":"Autophagy Induction by the Pathogen Receptor CD46","volume":"6","author":"Joubert","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12969","DOI":"10.1038\/s41598-018-30447-0","article-title":"Investigation of Novel Regulation of N-Myristoyltransferase by Mammalian Target of Rapamycin in Breast Cancer Cells","volume":"8","author":"Jacquier","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1080\/15548627.2019.1603547","article-title":"Emerging Views of Mitophagy in Immunity and Autoimmune Diseases","volume":"16","author":"Xu","year":"2019","journal-title":"Autophagy"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mito.2017.10.009","article-title":"Mitophagy and the Release of Inflammatory Cytokines","volume":"41","author":"Harris","year":"2018","journal-title":"Mitochondrion"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1097\/MPG.0b013e3181818fb9","article-title":"Celiac Disease Pathogenesis: The Proinflammatory Cytokine Network","volume":"47","author":"Garrote","year":"2008","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s12013-012-9499-y","article-title":"Regulation of Involucrin in Psoriatic Epidermal Keratinocytes: The Roles of ERK1\/2 and GSK-3\u03b2","volume":"66","author":"Chen","year":"2013","journal-title":"Cell Biochem. Biophys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1038\/nprot.2006.468","article-title":"In-gel digestion for mass spectrometric characterization of proteins and proteomes","volume":"1","author":"Shevchenko","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D1107","DOI":"10.1093\/nar\/gkw1080","article-title":"jPOSTrepo: An International Standard Data Repository for Proteomes","volume":"45","author":"Okuda","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D730","DOI":"10.1093\/nar\/gkae1113","article-title":"The STRING Database in 2025: Protein Networks with Directionality of Regulation","volume":"53","author":"Szklarczyk","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A Graphical Gene-Set Enrichment Tool for Animals and Plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 Web Portal for Protein Modelling, Prediction and Analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T04:14:22Z","timestamp":1778386462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093938"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093938","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]}}}