{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:35:17Z","timestamp":1791725717702,"version":"4.3.4"},"reference-count":80,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2019,6,30]],"date-time":"2019-06-30T00:00:00Z","timestamp":1561852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003542","name":"Ministerium f\u00fcr Wissenschaft, Forschung und Kunst Baden-W\u00fcrttemberg","doi-asserted-by":"publisher","award":["32-7533-6-10\/15\/5"],"award-info":[{"award-number":["32-7533-6-10\/15\/5"]}],"id":[{"id":"10.13039\/501100003542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["175083951"],"award-info":[{"award-number":["175083951"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Pulmosens GRK2203"],"award-info":[{"award-number":["Pulmosens GRK2203"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Interleukin-13 (IL-13) drives symptoms in asthma with high levels of T-helper type 2 cells (Th2-cells). Since tight junctions (TJ) constitute the epithelial diffusion barrier, we investigated the effect of IL-13 on TJ in human tracheal epithelial cells. We observed that IL-13 increases paracellular permeability, changes claudin expression pattern and induces intracellular aggregation of the TJ proteins zonlua occludens protein 1, as well as claudins. Furthermore, IL-13 treatment increases expression of ubiquitin conjugating E2 enzyme UBE2Z. Co-localization and proximity ligation assays further showed that ubiquitin and the proteasomal marker PSMA5 co-localize with TJ proteins in IL-13 treated cells, showing that TJ proteins are ubiquitinated following IL-13 exposure. UBE2Z upregulation occurs within the first day after IL-13 exposure. Proteasomal aggregation of ubiquitinated TJ proteins starts three days after IL-13 exposure and transepithelial electrical resistance (TEER) decrease follows the time course of TJ-protein aggregation. Inhibition of JAK\/STAT signaling abolishes IL-13 induced effects. Our data suggest that that IL-13 induces ubiquitination and proteasomal aggregation of TJ proteins via JAK\/STAT dependent expression of UBE2Z, resulting in opening of TJs. This may contribute to barrier disturbances in pulmonary epithelia and lung damage of patients with inflammatory lung diseases.<\/jats:p>","DOI":"10.3390\/ijms20133222","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T03:23:59Z","timestamp":1561951439000},"page":"3222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["IL-13 Impairs Tight Junctions in Airway Epithelia"],"prefix":"10.3390","volume":"20","author":[{"given":"Hanna","family":"Schmidt","sequence":"first","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Braubach","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 130625 Hannover, Germany"},{"name":"German Center of Lung Research (DZL), Partnersite BREATH, 306245 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Schilpp","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Lochbaum","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Neuland","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Thompson","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Jonigk","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 130625 Hannover, Germany"},{"name":"German Center of Lung Research (DZL), Partnersite BREATH, 306245 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4763-1104","authenticated-orcid":false,"given":"Manfred","family":"Frick","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Dietl","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-6471","authenticated-orcid":false,"given":"Oliver H.","family":"Wittekindt","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.jaci.2010.11.037","article-title":"Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome","volume":"127","author":"Akdis","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/cea.12880","article-title":"Revisiting Type 2-high and Type 2-low airway inflammation in asthma: Current knowledge and therapeutic implications","volume":"47","author":"Robinson","year":"2017","journal-title":"Clin. Exp. Allergy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3109\/08830189809043004","article-title":"The concept of type-1 and type-2 helper T cells and their cytokines in humans","volume":"16","year":"1998","journal-title":"Int. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1172\/JCI5909","article-title":"Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production","volume":"103","author":"Zhu","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1126\/science.282.5397.2258","article-title":"Interleukin-13: Central mediator of allergic asthma","volume":"282","author":"Luyimbazi","year":"1998","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1136\/thoraxjnl-2014-206719","article-title":"Lebrikizumab in moderate-to-severe asthma: Pooled data from two randomised placebo-controlled studies","volume":"70","author":"Hanania","year":"2015","journal-title":"Thorax"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/S2213-2600(15)00197-6","article-title":"Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: A randomised, double-blind, placebo-controlled, phase 2b trial","volume":"3","author":"Brightling","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/cpt.803","article-title":"Dose-exposure-response relationship of the investigational anti-interleukin-13 monoclonal antibody tralokinumab in patients with severe, uncontrolled asthma","volume":"103","author":"Baverel","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5219","DOI":"10.4049\/jimmunol.166.8.5219","article-title":"Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma","volume":"166","author":"Blease","year":"2001","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1007\/s12325-017-0525-8","article-title":"RPC4046, a novel anti-interleukin-13 antibody, blocks IL-13 binding to IL-13 \u03b11 and \u03b12 receptors: A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study","volume":"34","author":"Tripp","year":"2017","journal-title":"Adv. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1165\/rcmb.2017-0200TR","article-title":"Airway epithelial barrier dysfunction in chronic obstructive pulmonary disease: Role of cigarette smoke exposure","volume":"58","author":"Aghapour","year":"2018","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2174\/1566524018666181109121849","article-title":"Role of HIF-1 in cancer progression: Novel insights. A review","volume":"18","author":"Pezzuto","year":"2018","journal-title":"Curr. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"649","DOI":"10.2217\/fon.13.32","article-title":"New molecular insights in tobacco-induced lung cancer","volume":"9","author":"Tonini","year":"2013","journal-title":"Future Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cellsig.2016.12.006","article-title":"Cigarette smoke extracts induce overexpression of the proto-oncogenic gene interleukin-13 receptor \u03b12 through activation of the PKA-CREB signaling pathway to trigger malignant transformation of lung vascular endothelial cells and angiogenesis","volume":"31","author":"Meng","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1165\/ajrcmb.26.2.4600","article-title":"The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells","volume":"26","author":"Venkayya","year":"2002","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"L44","DOI":"10.1152\/ajplung.00296.2001","article-title":"Effects of IL-13 on airway responses in the guinea pig","volume":"282","author":"Morse","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L58","DOI":"10.1152\/ajplung.00157.2018","article-title":"Inflammation-induced upregulation of P2X4 expression augments mucin secretion in airway epithelia","volume":"316","author":"Winkelmann","year":"2019","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1111\/j.1365-2222.2011.03852.x","article-title":"IL-13-induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells","volume":"41","author":"Kanoh","year":"2011","journal-title":"Clin. Exp. Allergy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1136\/thoraxjnl-2014-205731","article-title":"Tiotropium attenuates IL-13-induced goblet cell metaplasia of human airway epithelial cells","volume":"70","author":"Kistemaker","year":"2015","journal-title":"Thorax"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.intimp.2017.03.005","article-title":"Therapeutic efficacy of a co-blockade of IL-13 and IL-25 on airway inflammation and remodeling in a mouse model of asthma","volume":"46","author":"Zhang","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1164\/ajrccm\/145.6.1469","article-title":"Airway hyperresponsiveness, increased intracellular spaces of bronchial epithelium, and increased infiltration of eosinophils and lymphocytes in bronchial mucosa in asthma","volume":"145","author":"Ohashi","year":"1992","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/alr.21298","article-title":"Interleukin-4 and interleukin-13 compromise the sinonasal epithelial barrier and perturb intercellular junction protein expression","volume":"4","author":"Wise","year":"2014","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jaci.2016.03.050","article-title":"Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients","volume":"139","author":"Wawrzyniak","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","first-page":"1","article-title":"Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma","volume":"139","author":"Sweerus","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e24333","DOI":"10.4161\/tisb.24333","article-title":"Interleukin-4 and interleukin-13 cause barrier dysfunction in human airway epithelial cells","volume":"1","author":"Saatian","year":"2013","journal-title":"Tissue Barriers"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"C2029","DOI":"10.1152\/ajpcell.2001.281.6.C2029","article-title":"Lung epithelial barrier function and wound healing are decreased by IL-4 and IL-13 and enhanced by IFN-gamma","volume":"281","author":"Ahdieh","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00424-016-1909-3","article-title":"Claudins: Vital partners in transcellular and paracellular transport coupling","volume":"469","year":"2017","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.semcdb.2015.04.009","article-title":"Claudins: Gatekeepers of lung epithelial function","volume":"42","author":"Schlingmann","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/alr.21077","article-title":"Epithelial permeability alterations in an in vitro air-liquid interface model of allergic fungal rhinosinusitis","volume":"3","author":"Hoddeson","year":"2013","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1172\/JCI112743","article-title":"Protein permeability in the adult respiratory distress syndrome. Loss of size selectivity of the alveolar epithelium","volume":"78","author":"Holter","year":"1986","journal-title":"J. Clin. Invest."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1513\/AnnalsATS.201507-421MG","article-title":"Airway epithelial orchestration of innate immune function in response to virus infection. A focus on asthma","volume":"13","author":"Ritchie","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1476-9255-7-41","article-title":"Anti-inflammatory activity and neutrophil reductions mediated by the JAK1\/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis","volume":"7","author":"Meyer","year":"2010","journal-title":"J. Inflamm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/cmdc.201300520","article-title":"Design and synthesis of tricyclic jak3 inhibitors with picomolar affinities as novel molecular probes","volume":"9","author":"Gehringer","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5298","DOI":"10.4049\/jimmunol.0902819","article-title":"Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: Preclinical characterization of INCB028050","volume":"184","author":"Fridman","year":"2010","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3109","DOI":"10.1182\/blood-2009-04-214957","article-title":"Preclinical characterization of the selective JAK1\/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms","volume":"115","author":"Vaddi","year":"2010","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"18010","DOI":"10.1073\/pnas.1009399107","article-title":"Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization","volume":"107","author":"Hou","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1165\/rcmb.2015-0071OC","article-title":"Glucocorticoids regulate tight junction permeability of lung epithelia by modulating claudin 8","volume":"54","author":"Kielgast","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1083\/jcb.110.2.349","article-title":"Identification of a membrane-cytoskeleton complex containing the cell adhesion molecule uvomorulin (E-Cadherin), ankyrin, and fodrin in Madin-Darby canine kidney epithelial cells","volume":"110","author":"Nelson","year":"1990","journal-title":"J. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0092-8674(94)90396-4","article-title":"The ubiquitin-proteasome proteolytic pathway","volume":"79","author":"Ciechanover","year":"1994","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4340","DOI":"10.1073\/pnas.1421441112","article-title":"KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8","volume":"112","author":"Gong","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.mce.2005.12.021","article-title":"Regulation of junction dynamics in the testis\u2014Transcriptional and post-translational regulations of cell junction proteins","volume":"250","author":"Lui","year":"2006","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/jcp.20254","article-title":"cAMP perturbs inter-Sertoli tight junction permeability barrier in vitro via its effect on proteasome-sensitive ubiquitination of occludin","volume":"203","author":"Wing","year":"2005","journal-title":"J. Cell. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1002\/jcb.24118","article-title":"The ubiquitin-proteasome pathway regulates claudin 5 degradation","volume":"113","author":"Mandel","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.devcel.2011.08.003","article-title":"Dlg3 Trafficking and apical tight junction formation is regulated by Nedd4 and Nedd4-2 E3 Ubiquitin ligases","volume":"21","author":"Eitelhuber","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10201","DOI":"10.1074\/jbc.M111384200","article-title":"The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch","volume":"277","author":"Traweger","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1242\/jcs.109.4.787","article-title":"Partial colocalization of glucocorticoid and mineralocorticoid receptors in discrete compartments in nuclei of rat hippocampus neurons","volume":"109","author":"Hornsby","year":"1996","journal-title":"J. Cell Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jaci.2014.06.035","article-title":"Biological clustering supports both \u201cdutch\u201d and \u201cbritish\u201d hypotheses of asthma and chronic obstructive pulmonary disease","volume":"135","author":"Ghebre","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.jaci.2017.02.038","article-title":"Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients","volume":"141","author":"Sugita","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.cyto.2015.05.018","article-title":"Strategies targeting the IL-4\/IL-13 axes in disease","volume":"75","author":"May","year":"2015","journal-title":"Cytokine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/mi.2017.52","article-title":"Tricellulin is regulated via interleukin-13-receptor \u03b12, affects macromolecule uptake, and is decreased in ulcerative colitis","volume":"11","author":"Krug","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Skieterska, K., Rondou, P., and Van Craenenbroeck, K. (2017). Regulation of G protein-coupled receptors by ubiquitination. Int. J. Mol. Sci., 18.","DOI":"10.20944\/preprints201704.0135.v1"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1096\/fasebj.11.14.9409540","article-title":"Ubiquitin-dependent internalization regulation of plasma membrane proteins","volume":"11","author":"Hicke","year":"1997","journal-title":"FASEB J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnmol.2017.00347","article-title":"Regulation of AMPA receptor trafficking by protein ubiquitination","volume":"10","author":"Widagdo","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.beha.2017.09.001","article-title":"Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting","volume":"30","author":"Ciechanover","year":"2017","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1242\/jcs.040055","article-title":"The E3 ubiquitin ligase LNX1p80 promotes the removal of claudins from tight junctions in MDCK cells","volume":"122","author":"Takahashi","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1242\/jcs.165878","article-title":"Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells","volume":"128","author":"Cong","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"21036","DOI":"10.1074\/jbc.M109.016766","article-title":"Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability","volume":"284","author":"Murakami","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s00018-016-2352-5","article-title":"SUMOylation regulates the intracellular fate of ZO-2","volume":"74","author":"Wetzel","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1111\/j.1600-0854.2011.01243.x","article-title":"Derlin-dependent retrograde transport from endosomes to the golgi apparatus","volume":"12","author":"Dang","year":"2011","journal-title":"Traffic"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1242\/jcs.048892","article-title":"Derlin-dependent accumulation of integral membrane proteins at cell surfaces","volume":"122","author":"Schaheen","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s11033-006-9033-7","article-title":"Cloning and characterization of a gene encoding the human putative ubiquitin conjugating enzyme E2Z (UBE2Z)","volume":"34","author":"Gu","year":"2007","journal-title":"Mol. Biol. Rep."},{"key":"ref_62","first-page":"1","article-title":"Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes","volume":"8","author":"Liu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/nature05902","article-title":"Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging","volume":"447","author":"Jin","year":"2007","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00441-014-1994-6","article-title":"Defects in the adherens junction complex (E-cadherin\/ \u03b2-catenin) in inflammatory bowel disease","volume":"360","author":"Mehta","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.pneurobio.2013.10.003","article-title":"Role of the ubiquitin-proteasome system in brain ischemia: Friend or foe?","volume":"112","author":"Caldeira","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms10963","article-title":"Open-gate mutants of the mammalian proteasome show enhanced ubiquitin-conjugate degradation","volume":"7","author":"Choi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1111\/j.1432-1033.1992.tb16961.x","article-title":"Demonstration that a human 26S proteolytic complex consists of a proteasome and multiple associated protein components and hydrolyzes ATP and ubiquitin-ligated proteins by closely linked mechanisms","volume":"206","author":"Kanayama","year":"1992","journal-title":"Eur. J. Biochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1126\/science.1141448","article-title":"Adapting proteostatis for disease intervention","volume":"319","author":"Balch","year":"2008","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.1365-2249.2008.03872.x","article-title":"The effect of proteasome inhibitor MG132 on experimental inflammatory bowel disease","volume":"156","author":"Inoue","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1378\/chest.11-1660","article-title":"Ubiquitination and proteolysis in acute lung injury","volume":"141","author":"Weiss","year":"2012","journal-title":"Chest"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2466-14-187","article-title":"Genes related to emphysema are enriched for ubiquitination pathways","volume":"14","author":"Stepaniants","year":"2014","journal-title":"BMC Pulm. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00109-011-0732-8","article-title":"Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema","volume":"89","author":"Min","year":"2011","journal-title":"J. Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1165\/rcmb.2014-0107OC","article-title":"Role of cigarette smoke-induced aggresome formation in chronic obstructive pulmonary disease-emphysema pathogenesis","volume":"53","author":"Tran","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1165\/rcmb.2014-0377OC","article-title":"Mitochondrial E3 ubiquitin protein ligase 1 mediates cigarette smoke-induced endothelial cell death and dysfunction","volume":"54","author":"Kim","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1056\/NEJM200005043421806","article-title":"The acute respiratory distress syndrome","volume":"342","author":"Ware","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1165\/rcmb.2013-0353OC","article-title":"Knockout mice reveal key roles for Claudin 18 in alveolar barrier properties and fluid homeostasis","volume":"51","author":"Li","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"L524","DOI":"10.1152\/ajplung.00077.2014","article-title":"Claudin 4 knockout mice: Normal physiological phenotype with increased susceptibility to lung injury","volume":"307","author":"Kage","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1165\/rcmb.2005-0474OC","article-title":"Persistent effects induced by IL-13 in the lung","volume":"35","author":"Fulkerson","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/mrd.22489","article-title":"The ImageJ ecosystem: An open platform for biomedical image analysis","volume":"82","author":"Schindelin","year":"2015","journal-title":"Mol. Reprod. 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