Luciani Alessandro, Villella Valeria Rachela, Vasaturo Angela, Giardino Ida, Raia Valeria, Pettoello-Mantovani Massimo, D'Apolito Maria, Guido Stefano, Leal Teresinha, Quaratino Sonia, Maiuri Luigi
Institute of Pediatrics, University of Foggia, Foggia, Italy.
J Immunol. 2009 Aug 15;183(4):2775-84. doi: 10.4049/jimmunol.0900993. Epub 2009 Jul 22.
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.
囊性纤维化（CF）是一种由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起的单基因疾病。CF的特征是慢性细菌性肺部感染和炎症，我们之前报道过，组织转谷氨酰胺酶（TG2）是一种对多种疾病至关重要的多功能酶，在CF气道中持续上调并驱动慢性炎症。在此，我们证明CFTR功能缺陷诱导产生的氧化应激导致信号转导和转录激活因子（STAT）激活蛋白的蛋白抑制剂（PIAS）y介导的TG2小泛素样修饰（SUMO）化，并抑制TG2泛素化和蛋白酶体降解，从而导致TG2持续激活。这会阻止过氧化物酶体增殖物激活受体（PPAR）γ和IκBα的SUMO化，导致核因子κB（NF-κB）激活以及不受控制的炎症反应。通过小泛素样修饰物（SUMO）-1或PIASy基因沉默可恢复细胞内稳态，这会诱导TG2泛素化和蛋白酶体降解，恢复PPARγ的SUMO化，并防止IκBα交联和降解，从而消除炎症。锰超氧化物歧化酶的过表达以及用合成超氧化物歧化酶模拟物EUK-134进行处理可控制PIASy-TG2相互作用和TG2的SUMO化。在纯合F508del-CFTR小鼠模型中，TG2抑制在体外和体内均可消除炎症。因此，TG2可能通过决定蛋白质是应进行SUMO介导的调节还是降解，在氧化应激和炎症之间起连接作用。靶向TG2-SUMO相互作用可能是控制CF患者以及其他慢性炎症性疾病、神经退行性病变和癌症疾病进展的新选择。
