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

Sladitschek-Martens, Hanna Lucie; Guarnieri, Alberto; Brumana, Giulia; Zanconato, Francesca; Battilana, Giusy; Xiccato, Romy Lucon; Panciera, Tito; Forcato, Mattia; Bicciato, Silvio; Guzzardo, Vincenza; Fassan, Matteo; Ulliana, Lorenzo; Gandin, Alessandro; Tripodo, Claudio; Foiani, Marco; Brusatin, Giovanna; Cordenonsi, Michelangelo; Piccolo, Stefano

doi:10.1038/s41586-022-04924-6

Cited by 113 publications

(137 citation statements)

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“…To interrogate why senescent MSC proteomes appeared to behave as if they were on a stiffer substrate we next sought to identify which mechanosensitive elements were altered during senescence. YAP/TAZ signalling has previously been linked to ageing and senescence in mice (Fu et al , 2019; Sladitschek-Martens et al , 2022; Xu et al , 2021). While we didn’t observe any significant change in YAP1 transcript levels (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of cytoskeletal proteostasis links dysregulation of cell size and mechanotransduction in mesenchymal stem cell senescence

Mallikarjun

Dobre

Jackson

et al. 2022

Preprint

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Tissues are maintained by homeostatic feedback mechanisms where cells respond to, but also modify, the chemical and mechanical properties of the surrounding extracellular matrix. Mesenchymal stem cells (MSCs) resident in the marrow niche experience a diverse mechanical environment, but ageing can affect the composition and quality of bone and marrow tissues. Here we quantified the effect of replication-induced senescence on MSC morphology and their ability to correctly respond to different substrate stiffnesses. The matrix proteome was found to be sensitive to substrate stiffness, but pharmacological inhibition of cellular contractility perturbed this response, decreasing levels of tenascin-C, fibulins and fibronectin. Similar decreases in these mechanosensitive proteins were observed in senescent cells, suggested a decoupling of mechanotransduction pathways. Intracellular proteomic and transcriptomic analyses confirmed a decrease in components of the cytoskeletal chaperone complex CCT/TRiC in senescent MSCs. Finally, pharmacological inhibition of CCT/TRiC was able to partially recapitulate senescence-associated morphological changes in non-senescent MSCs. These results demonstrate a senescence-mediated perturbation to cytoskeletal homeostasis, pathways of mechanotransduction and the secretion of matrix proteins required for tissue maintenance.

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Section: Resultsmentioning

confidence: 99%

Loss of cytoskeletal proteostasis links dysregulation of cell size and mechanotransduction in mesenchymal stem cell senescence

Mallikarjun

Dobre

Jackson

et al. 2022

Preprint

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“…When the Hippo pathway is inactive, YAP and TAZ translocate into the nucleus and interact with transcription factors to regulate the expression of target genes. Previous works also manifested the effectiveness of YAP and TAZ in cellular senescence [ 32 ]. However, it seems that in various types of cells, the effects of YAP in modulating cellular senescence are quite different.…”

Section: Discussionmentioning

confidence: 99%

PCAF Accelerates Vascular Senescence via the Hippo Signaling Pathway

Kong

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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P300/CBP-Associated Factor (PCAF), one of the histone acetyltransferases (HATs), is known to be involved in cell growth and/or differentiation. PCAF is reported to be involved in atherosclerotic plaques and neointimal formation. However, its role in cellular senescence remains undefined. We investigated the potential mechanism for PCAF-mediated cellular senescence. Immunohistochemical (IHC) analysis showed PCAF was distinctly increased in the endothelia of aorta in aged mice. Palmitate acid (PA) or X radiation significantly induced the expression of senescence-associated markers and PCAF in human umbilical vein endothelial cells (HUVECs). PCAF silence in PA-treated HUVECs significantly rescued senescence-associated phenotypes, while PCAF overexpression accelerated it. Additionally, our results showed that Yes1 Associated Transcriptional Regulator (YAP) that acts as end effector of the Hippo signaling pathway is crucial in PCAF-mediated endothelial senescence. YAP activity declining was observed in aged vascular endothelia. Overexpression of YAP partially ameliorated PCAF-induced endothelial senescence. In vivo, endothelial-(EC-) specific PCAF downregulation in aged mice using adeno-associated virus revealed less vascular senescence-associated phenotypes. These results suggested that PCAF mediated endothelial senescence through the Hippo signaling pathway, implying that PCAF may become a potential target for the prevention and treatment of vascular aging.

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“…Cellular senescence is a concerted process that involves a stable cell cycle arrest despite continued metabolic activity, and the development of a pro-inflammatory response known as the senescence-associated secretory phenotype (SASP) [1] . Aging and senescence have long been associated, and studies employing senolytic approaches, i.e., the targeted removal of senescent cells, have demonstrated a causal role for their actions in aging-related phenotypes in various tissues [2] . Presumably, due to the nature of SASP, this process is largely non-cell autonomous and involves paracrine effects on neighboring cells to promote organ dysfunction.…”

mentioning

confidence: 99%

“…Senescent cell accumulation is linked to aging, and senolytic approaches ameliorate aging-related tissue degeneration [1,2] . The study from Sladitschek-Martens et al elegantly linked physiological aging and cellular senescence to a decline in mechanotransduction mediated by decreased YAP/TAZ activity [3] .…”

mentioning

confidence: 99%

“…A recent study from Sladitschek-Martens et al published in Nature , tested the possibility that altered mechanosensing of the extracellular environment, i.e., the extracellular matrix (ECM), is a signal for physiological aging [ 3 ] . The transcriptional coactivators and end effectors of the Hippo signaling pathway, YAP and TAZ, are established mediators that link mechanosensation to changes in cell behavior through the regulation of transcriptional programs [ 4 , 5 ] .…”

mentioning

confidence: 99%

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