Matrix stiffness‐induced α‐tubulin acetylation is required for skin fibrosis formation through activation of Yes‐associated protein

Abstract

Skin fibrosis, a pathological process featured by fibroblast activation and extracellular matrix (ECM) deposition, makes a significant contribution to morbidity. Studies have identified biomechanics as the central element in the complex network of fibrogenesis that drives the profibrotic feedback loop. In this study, we found that the acetylation of α‐tubulin at lysine 40 (K40) was augmented in fibrotic skin tissues. Further analysis showed that α‐tubulin acetylation is required for fibroblast activation, including contraction, migration, and ECM deposition. More importantly, we revealed that biomechanics‐induced upregulation of K40 acetylation promotes fibrosis by mediating mechanosensitive Yes‐associated protein S127 dephosphorylation and its cytoplasm nucleus shuttle. Furthermore, we demonstrated that the knockdown of α‐tubulin acetyltransferase 1 could rescue the K40 acetylation upregulation caused by increased matrix rigidity and ameliorate skin fibrosis both in vivo and in vitro. Herein, we highlight the critical role of α‐tubulin acetylation in matrix stiffness‐induced skin fibrosis and clarify a possible molecular mechanism. Our research suggests α‐tubulin acetylation as a potential target for drug design and therapeutic intervention.

Survival-Associated Cellular Response Maintained in Pancreatic Ductal Adenocarcinoma (PDAC) Switched Between Soft and Stiff 3D Microgel Culture

“…Cells primed in stiff conditions expressed statistically ( p < 0.01) higher levels of RAC3 compared to those primed in soft conditions ( Figure 7 d). Additional evidence of mechanosensation was observed as differences in radial acetylated-tubulin expression, 82 − 87 with soft-cultured cells exhibiting membrane-localized tubulin and stiff-cultured cells exhibiting tubulin expression throughout the cell body after 24 h ( Figures S10 and S11 ). Microtubule acetylation has been shown to play a role in mechanosensitive adhesion and migration through focal adhesions and YAP translocation and can promote traction forces via actomyosin contractility.…”

“…Cells primed in stiff conditions expressed statistically ( p < 0.01) higher levels of RAC3 compared to those primed in soft conditions (Figure d). Additional evidence of mechanosensation was observed as differences in radial acetylated-tubulin expression, − with soft-cultured cells exhibiting membrane-localized tubulin and stiff-cultured cells exhibiting tubulin expression throughout the cell body after 24 h (Figures S10 and S11). Microtubule acetylation has been shown to play a role in mechanosensitive adhesion and migration through focal adhesions and YAP translocation and can promote traction forces via actomyosin contractility. , Microtubules have also been shown to regulate nuclear invaginations, and these precise shape changes have been shown to direct loss of chromatin accessibility, changes in gene expression, and phenotypic changes. − Together, our results support our hypothesis that PDAC cells cultured in 3D microgel environments maintain persistent cellular responses to mechanical conditioning at both the RNA and protein levels.…”

“…Microtubule acetylation has been shown to play a role in mechanosensitive adhesion and migration through focal adhesions and YAP translocation and can promote traction forces via actomyosin contractility. 82 , 84 Microtubules have also been shown to regulate nuclear invaginations, and these precise shape changes have been shown to direct loss of chromatin accessibility, changes in gene expression, and phenotypic changes. 85 − 87 Together, our results support our hypothesis that PDAC cells cultured in 3D microgel environments maintain persistent cellular responses to mechanical conditioning at both the RNA and protein levels.…”