Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis

ABSTRACT: Tissue mechanical homeostasis, the concept that cells sense mechanical properties and alter rates of ECM synthesis, assembly and degradation, is of broad interest in biology and medicine, but there is little direct support or insight into mechanisms. Tissue mechanical properties such as elasticity and stiffness are determined primarily by the extracellular matrix (ECM). We therefore set out to test the mechanical homeostasis hypothesis by developing mutations in the mechanosensitive protein talin1 that alter cells’ sensing of ECM stiffness. We identified the side-to-side interaction between talin1 rod domain helix bundles 1 and 2 (R1 and R2) as a novel mechanosensitive site. Mutations that decrease the affinity of the interaction result in a leftward shift in cellular stiffness sensing curves, enabling cells to spread and exert tension on softer substrates. Opening of the R1-R2 interface promotes binding of the Arp2/3 subunit ArpC5L, which is required for the altered stiffness sensing. Introduction of these talin mutations into mice resulted in softer tissue in the ascending aorta with less fibrillar collagen and rupture under lower pressure ex vivo. Together, these results demonstrate that altering cellular stiffness sensing results in altered ECM deposition, tissue stiffness and strength, thus providing direct support for the mechanical homeostasis hypothesis. These results also identify a novel mechanosensitive interaction in the talin rod domain that contributes to this mechanism.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: TuKiet Lam  

LAB HEAD: TuKiet Lam

PROVIDER: PXD041630 | Pride | 2024-07-16

REPOSITORIES: Pride