Ageing is intimately connected to the induction of cell senescence(1,2), but why this is so remains poorly understood. A key challenge isthe identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing(3). 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 oftissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, tothe extent that inhibition of STING preventstissue 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 Bland 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.

Hanna Lucie Sladitschek-Martens, Alberto Guarnieri, Giulia Brumana, Francesca Zanconato, Giusy Battilana, Romy Lucon Xiccato, et al. (2022). YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING. NATURE, 607(7920), 790-+ [10.1038/s41586-022-04924-6].

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

Claudio Tripodo;
2022-01-01

Abstract

Ageing is intimately connected to the induction of cell senescence(1,2), but why this is so remains poorly understood. A key challenge isthe identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing(3). 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 oftissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, tothe extent that inhibition of STING preventstissue 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 Bland 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.
Settore MED/08 - Anatomia Patologica
Hanna Lucie Sladitschek-Martens, Alberto Guarnieri, Giulia Brumana, Francesca Zanconato, Giusy Battilana, Romy Lucon Xiccato, et al. (2022). YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING. NATURE, 607(7920), 790-+ [10.1038/s41586-022-04924-6].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/578964
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