YAP and TAZ in Cell Structure and Cell Senescence
This scientific commentary describes an interesting join the dots exercise in which scientists link together a number of different topics that have shown up over the years in research into aging. Here, the Hippo pathway (activated by YAP and TAZ), the shape and maintenance of the nuclear envelope, inflammatory cGAS/STING signaling, and cellular senescence are all connected. Declining expression of YAP and TAZ occur with aging, for reasons to be explored, and that decline appears sufficient in and of itself to trigger the rest of the linked cascade of changes and consequent cellular senescence and tissue dysfunction.
A recent study tested the possibility that altered mechanosensing of the extracellular environment, i.e., the extracellular matrix (ECM), is a signal for physiological aging. 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.
To explore the hypothesis that YAP/TAZ mediate effects of aging, the authors first performed a series of experiments employing single-cell RNA-seq data that indicated the downregulation of a YAP/TAZ activation signature gene set in dermal fibroblasts of old mice. This pattern of depressed YAP/TAZ activity was also observed in other stromal cells (e.g., kidney fibroblasts) as well as contractile cells (cardiomyocytes, vascular smooth muscle cells) but not in epithelial cells, hepatocytes, or lymphocytes, indicating cell-type specificity.
Depletion of YAP/TAZ in young mice reduced dermal fibroblast number and phenocopied aged skin in control mice. Targeted deletion of YAP/TAZ in vascular smooth muscle cells elicited aortic dissection, rupture, and death in several weeks, thereby accelerating aging-associated pathology. To further substantiate YAP/TAZ regulation of cellular senescence, transcriptome profiling in freshly isolated dermal fibroblasts from young mice demonstrated increased senescence-associated secretory phenotype (SASP) genes as well as increased β-gal expression, both hallmarks of senescence, in YAP/TAZ deficient cells. On the other hand, supplementing YAP to fibroblasts cultured from old mice led to suppression of SASP and β-gal positivity.
cGAS-STING signaling modulates innate immune responses and has been previously implicated in the regulation of senescence. Through multiple complementary approaches, researchers showed that YAP/TAZ suppressed cGAS activation in several cell and tissue types, and involved the inappropriate release of genomic DNA into the cytosol. How does YAP/TAZ restrain cGAS-STING? The authors astutely recognized a relationship between decreased YAP/TAZ activity and distorted nuclear architecture in old cells. Moreover, the addition of active YAP rescued abnormal nuclear structure caused by aging. Additional screens revealed that YAP/TAZ directly promote the expression of two key factors that maintain proper nuclear envelope integrity, lamin B1 and ACTR2.
These findings demonstrate that YAP/TAZ is a critical upstream modulator of nuclear integrity and functions in young cells to keep cGAS-STING in check to prevent the aging phenotype of cellular senescence.