SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation.
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.
Luciani
Alessandro
A
Institute of Pediatrics, University of Foggia, Foggia, Italy.
Villella
Valeria Rachela
VR
Vasaturo
Angela
A
Giardino
Ida
I
Raia
Valeria
V
Pettoello-Mantovani
Massimo
M
D'Apolito
Maria
M
Guido
Stefano
S
Leal
Teresinha
T
Quaratino
Sonia
S
Maiuri
Luigi
L
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
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