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

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

Research output: Contribution to journalArticle

10 Citations (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.

Original languageEnglish
Article numbere45067
JournalEMBO Reports
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

Fingerprint

Heat-Shock Response
Post Translational Protein Processing
Shock
Hot Temperature
Cystic Fibrosis
Chemical activation
Protein Disulfide-Isomerases
Deregulation
Transcription
Heat-Shock Proteins
transglutaminase 2
Transcription Factors
Genes
Modulation
Defects
DNA

Keywords

  • Cystic fibrosis
  • HSF1
  • HSP70
  • proteostasis
  • TG2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Rossin, F., Villella, V. R., D'Eletto, M., Farrace, M. G., Esposito, S., Ferrari, E., ... Piacentini, M. (2018). TG2 regulates the heat-shock response by the post-translational modification of HSF1. EMBO Reports, 19(7), [e45067]. https://doi.org/10.15252/embr.201745067

TG2 regulates the heat-shock response by the post-translational modification of HSF1. / Rossin, Federica; Villella, Valeria Rachela; D'Eletto, Manuela; Farrace, Maria Grazia; Esposito, Speranza; Ferrari, Eleonora; Monzani, Romina; Occhigrossi, Luca; Pagliarini, Vittoria; Sette, Claudio; Cozza, Giorgio; Barlev, Nikolai A.; Falasca, Laura; Fimia, Gian Maria; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi; Piacentini, Mauro.

In: EMBO Reports, Vol. 19, No. 7, e45067, 01.07.2018.

Research output: Contribution to journalArticle

Rossin, F, Villella, VR, D'Eletto, M, Farrace, MG, Esposito, S, Ferrari, E, Monzani, R, Occhigrossi, L, Pagliarini, V, Sette, C, Cozza, G, Barlev, NA, Falasca, L, Fimia, GM, Kroemer, G, Raia, V, Maiuri, L & Piacentini, M 2018, 'TG2 regulates the heat-shock response by the post-translational modification of HSF1', EMBO Reports, vol. 19, no. 7, e45067. https://doi.org/10.15252/embr.201745067
Rossin F, Villella VR, D'Eletto M, Farrace MG, Esposito S, Ferrari E et al. TG2 regulates the heat-shock response by the post-translational modification of HSF1. EMBO Reports. 2018 Jul 1;19(7). e45067. https://doi.org/10.15252/embr.201745067
Rossin, Federica ; Villella, Valeria Rachela ; D'Eletto, Manuela ; Farrace, Maria Grazia ; Esposito, Speranza ; Ferrari, Eleonora ; Monzani, Romina ; Occhigrossi, Luca ; Pagliarini, Vittoria ; Sette, Claudio ; Cozza, Giorgio ; Barlev, Nikolai A. ; Falasca, Laura ; Fimia, Gian Maria ; Kroemer, Guido ; Raia, Valeria ; Maiuri, Luigi ; Piacentini, Mauro. / TG2 regulates the heat-shock response by the post-translational modification of HSF1. In: EMBO Reports. 2018 ; Vol. 19, No. 7.
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