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TG2 regulates the heat‐shock response by the post‐translational modification of HSF1
Author(s) -
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
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745067
Subject(s) - hsf1 , heat shock , posttranslational modification , heat shock protein , microbiology and biotechnology , shock (circulatory) , biology , chemistry , hsp70 , biochemistry , medicine , gene , enzyme
Heat‐shock factor 1 ( HSF 1) 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 HSF 1. We demonstrate that transglutaminase type 2 ( TG 2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF 1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG 2 loss of function correlates with a defect in the nuclear translocation of HSF 1 and in its DNA ‐binding ability to the HSP 70 promoter. We show that the inhibition of TG 2 restores the unbalance in HSF 1‐ HSP 70 pathway in cystic fibrosis ( CF ), a human disorder characterized by deregulation of proteostasis. The absence of TG 2 leads to an increase of about 40% in CFTR function in a new experimental CF mouse model lacking TG 2. Altogether, these results indicate that TG 2 plays a key role in the regulation of cellular proteostasis under stressful cellular conditions through the modulation of the heat‐shock response.