SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation

Alessandro Luciani, Valeria Rachela Villella, Angela Vasaturo, Ida Giardino, Valeria Raia, Massimo Pettoello-Mantovani, Maria D'Apolito, Stefano Guido, Teresinha Leal, Sonia Quaratino, Luigi Maiuri

Research output: Contribution to journalArticle

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)γ and IkBα SUMOylation, leading to NF-κB 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 PPARγ SUMOylation, and prevent IkBα 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.

Original languageEnglish
Pages (from-to)2775-2784
Number of pages10
JournalJournal of Immunology
Volume183
Issue number4
DOIs
Publication statusPublished - Aug 15 2009

    Fingerprint

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Luciani, A., Villella, V. R., Vasaturo, A., Giardino, I., Raia, V., Pettoello-Mantovani, M., D'Apolito, M., Guido, S., Leal, T., Quaratino, S., & Maiuri, L. (2009). SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation. Journal of Immunology, 183(4), 2775-2784. https://doi.org/10.4049/jimmunol.0900993