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EMBO Rep. 2018 May 11. pii: e45067. doi: 10.15252/embr.201745067. [Epub ahead of print]

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

Author information

1
Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
2
Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy.
3
Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
4
Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy.
5
Department of Molecular Medicine, University of Padua, Padova, Italy.
6
Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, Russia.
7
National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy.
8
Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy.
9
Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
10
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
11
Institut National de la Santé et de la Recherche Médicale, U1138, Paris, France.
12
Université Pierre et Marie Curie, Paris, France.
13
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
14
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
15
Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
16
Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
17
SCDU of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
18
Department of Biology, University of Rome 'Tor Vergata', Rome, Italy mauro.piacentini@uniroma2.it.

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.

KEYWORDS:

Cystic fibrosis; HSF1; HSP70; TG2; proteostasis

PMID:
29752334
DOI:
10.15252/embr.201745067

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