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* Institute of Pediatrics, University of Foggia, Foggia, Italy;
Dynamic Imaging Microscopy, Centro di Ingegneria Genetica, Naples, Italy;
Department of Chemical Engineering, University Federico II of Naples, Naples, Italy;
Department of Laboratory Medicine, University of Foggia, Foggia, Italy;
¶ Department of Pediatrics, University Federico II of Naples, Naples, Italy;
|| Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium;
# Cancer Research UK Oncology Unit, University of Southampton, Southampton, United Kingdom; and
** European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy
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)
and IkB
SUMOylation, leading to NF-
B 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 PPAR SUMOylation, and prevent IkB 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the European Institute for Research in Cystic Fibrosis, Cancer Research UK, Rothschild Trust, Coeliac UK, and Regione Campania (L.229/99) and Associazione Italiana Celiachia Puglia (N.1400/07).
2 Address correspondence and reprint requests to Prof. Luigi Maiuri, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, 20132 Milan, Italy. E-mail address: maiuri{at}unina.it
3 Abbreviations used in this paper: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; F508del, deletion of phenylalanine at residue 508; TG2, tissue transglutaminase; PPAR, peroxisome proliferator-activate receptor; ROS, reactive oxygen species; SUMO, small ubiquitin-like modifier; PIAS, protein inhibitor of activated STAT; NEMO, NF-B essential modulator; siRNA, small interfering RNA; MnSOD, manganese superoxide dismutase; FRET, fluorescence resonance energy transfer; N-CoR, nuclear co-repressor.
4 The online version of this article contains supplemental material.
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