title: SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation.
abstract: Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by chronic bacterial lung infections and inflammation, and we have previously reported that tissue transglutaminase (TG2), a multifunctional enzyme critical to several diseases, is constitutively up-regulated in CF airways and drives chronic inflammation. Here, we demonstrate that the generation of an oxidative stress induced by CFTR-defective function leads to protein inhibitor of activated STAT (PIAS)y-mediated TG2 SUMOylation and inhibits TG2 ubiquitination and proteasome degradation, leading to sustained TG2 activation. This prevents peroxisome proliferator-activated receptor (PPAR)gamma and IkBalpha SUMOylation, leading to NF-kappaB activation and to an uncontrolled inflammatory response. Cellular homeostasis can be restored by small ubiquitin-like modifier (SUMO)-1 or PIASy gene silencing, which induce TG2 ubiquitination and proteasome degradation, restore PPARgamma SUMOylation, and prevent IkBalpha cross-linking and degradation, thus switching off inflammation. Manganese superoxide dismutase overexpression as well as the treatment with the synthetic superoxide dismutase mimetic EUK-134 control PIASy-TG2 interaction and TG2 SUMOylation. TG2 inhibition switches off inflammation in vitro as well as in vivo in a homozygous F508del-CFTR mouse model. Thus, TG2 may function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or degradation. Targeting TG2-SUMO interactions might represent a new option to control disease evolution in CF patients as well as in other chronic inflammatory diseases, neurodegenerative pathologies, and cancer.
authors.affiliation: Institute of Pediatrics, University of Foggia, Foggia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Luciani
authors.forename: Valeria Rachela
authors.initials: VR
authors.lastname: Villella
authors.forename: Angela
authors.initials: A
authors.lastname: Vasaturo
authors.forename: Ida
authors.initials: I
authors.lastname: Giardino
authors.forename: Valeria
authors.initials: V
authors.lastname: Raia
authors.forename: Massimo
authors.initials: M
authors.lastname: Pettoello-Mantovani
authors.forename: Maria
authors.initials: M
authors.lastname: D'Apolito
authors.forename: Stefano
authors.initials: S
authors.lastname: Guido
authors.forename: Teresinha
authors.initials: T
authors.lastname: Leal
authors.forename: Sonia
authors.initials: S
authors.lastname: Quaratino
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003550:Cystic Fibrosis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D019204:GTP-Binding Proteins; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000276:immunology*; D000075223:Poly-ADP-Ribose Binding Proteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D050828:Protein Inhibitors of Activated STAT / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D025842:SUMO-1 Protein / Q000378:metabolism*; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D017382:Reactive Oxygen Species; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins