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.

YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING / H. Lucie Sladitschek-Martens, A. Guarnieri, G. Brumana, F. Zanconato, G. Battilana, R. Lucon Xiccato, T. Panciera, M. Forcato, S. Bicciato, V. Guzzardo, M. Fassan, L. Ulliana, A. Gandin, C. Tripodo, M. Foiani, G. Brusatin, M. Cordenonsi, S. Piccolo. - In: NATURE. - ISSN 0028-0836. - 607:7920(2022 Jul 28), pp. 790-824. [10.1038/s41586-022-04924-6]

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

C. Tripodo;M. Foiani;
2022

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.
YAP; TAZ; ageing; C-GAS; STING
Settore MEDS-04/A - Anatomia patologica
28-lug-2022
29-giu-2022
Article (author)
File in questo prodotto:
File Dimensione Formato  
s41586-022-04924-6_compressed.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 3.85 MB
Formato Adobe PDF
3.85 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
EMS158105(2).pdf

accesso aperto

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 10.34 MB
Formato Adobe PDF
10.34 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1129848
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 135
  • ???jsp.display-item.citation.isi??? 133
social impact