Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3

• Published in: Nature communications Vol. 7; no. 1; p. 11642
• Main Authors: Speight, Pam, Kofler, Michael, Szászi, Katalin, Kapus, András
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.05.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 14/19; 14/35; 38/70; 38/77; 38/89; 631/337/572; 631/80/128; 631/80/79/2066; 631/80/86; 82/29; 96/95; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11642

Myocardin-related transcription factor (MRTF) and TAZ are major mechanosensitive transcriptional co-activators that link cytoskeleton organization to gene expression. Despite many similarities in their regulation, their physical and/or functional interactions are unknown. Here we show that MRTF and TAZ associate partly through a WW domain-dependent mechanism, and exhibit multilevel crosstalk affecting each other’s expression, transport and transcriptional activity. Specifically, MRTF is essential for TAZ expression; TAZ and MRTF inhibit each other’s cytosolic mobility and stimulus-induced nuclear accumulation; they antagonize each other’s stimulatory effect on the α-smooth muscle actin (SMA) promoter, which harbours nearby cis-elements for both, but synergize on isolated TEAD-elements. Importantly, TAZ confers Smad3 sensitivity to the SMA promoter. Thus, TAZ is a context-dependent switch during mechanical versus mechano/chemical signalling, which inhibits stretch-induced but is indispensable for stretch+TGFβ-induced SMA expression. Crosstalk between these cytoskeleton-regulated factors seems critical for fine-tuning mechanical and mechanochemical transcriptional programmes underlying myofibroblast transition, wound healing and fibrogenesis. MRTF and TAZ are mechanosensitive transcriptional coactivators, but how they functionally interact is not clear. Here the authors show that MRFT and TAZ exhibit multilevel crosstalk in expression, transport and transcriptional activity; furthermore, TAZ confers sensitivity to TGFβ activation of the smooth muscle actin promoter.