YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS–STING

Hanna Lucie Sladitschek-Martens, Alberto Guarnieri, Giulia Brumana, Francesca Zanconato, Giusy Battilana, Romy Lucon Xiccato, Tito Panciera, Mattia Forcato, Silvio Bicciato, Vincenza Guzzardo, Matteo Fassan, Lorenzo Ulliana, Alessandro Gandin, Claudio Tripodo, Marco Foiani, Giovanna Brusatin, Michelangelo Cordenonsi and Stefano Piccolo ()
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Hanna Lucie Sladitschek-Martens: University of Padua
Alberto Guarnieri: University of Padua
Giulia Brumana: University of Padua
Francesca Zanconato: University of Padua
Giusy Battilana: University of Padua
Romy Lucon Xiccato: University of Padua
Tito Panciera: University of Padua
Mattia Forcato: University of Modena and Reggio Emilia
Silvio Bicciato: University of Modena and Reggio Emilia
Vincenza Guzzardo: University of Padua
Matteo Fassan: University of Padua
Lorenzo Ulliana: University of Padua
Alessandro Gandin: University of Padua
Claudio Tripodo: University of Palermo
Marco Foiani: IFOM ETS, the AIRC Institute of Molecular Oncology
Giovanna Brusatin: University of Padua
Michelangelo Cordenonsi: University of Padua
Stefano Piccolo: University of Padua

Nature, 2022, vol. 607, issue 7920, 790-798

Abstract: Abstract Ageing is intimately connected to the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS–STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS–STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing.

Date: 2022
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DOI: 10.1038/s41586-022-04924-6

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