TG2 regulates the heat-shock response by the post-translational modification of HSF1

Vittoria Pagliarini, Claudio Sette, Federica Rossin, Valeria Rachela Villella, Manuela D'Eletto, Maria Grazia Farrace, Speranza Esposito, Eleonora Ferrari, Romina Monzani, Luca Occhigrossi, Giorgio Cozza, Nikolai A Barlev, Laura Falasca, Gian Maria Fimia, Guido Kroemer, Valeria Raia, Luigi Maiuri, Mauro Piacentini

Risultato della ricerca: Contributo in rivistaArticolo in rivista

16 Citazioni (Scopus)

Abstract

Heat-shock factor 1 (HSF1) is the master transcription factor that regulates the response to proteotoxic stress by controlling the transcription of many stress-responsive genes including the heat-shock proteins. Here, we show a novel molecular mechanism controlling the activation of HSF1. We demonstrate that transglutaminase type 2 (TG2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG2 loss of function correlates with a defect in the nuclear translocation of HSF1 and in its DNA-binding ability to the HSP70 promoter. We show that the inhibition of TG2 restores the unbalance in HSF1-HSP70 pathway in cystic fibrosis (CF), a human disorder characterized by deregulation of proteostasis. The absence of TG2 leads to an increase of about 40% in CFTR function in a new experimental CF mouse model lacking TG2. Altogether, these results indicate that TG2 plays a key role in the regulation of cellular proteostasis under stressful cellular conditions through the modulation of the heat-shock response.
Lingua originaleEnglish
pagine (da-a)419-427
Numero di pagine9
RivistaEMBO Reports
Volume19
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Cystic fibrosis
  • HSF1
  • HSP70
  • TG2
  • proteostasis

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