The Nuclear Lamina Directs Cellular Mechanosensitivty

Solid tissue cells employ different means for probing the physical properties of their surroundings. Mechanisms of active cellular mechanosensitivity involve the propagation of forces outside-in along cytoskeletal filaments and the application of tension to the nucleus. The conversion of physical inputs into biochemical signaling is facilitated by tension-suppressed phosphorylation of polymerized lamin-A/C at the nuclear envelope, disassembly and downstream protein turnover. While physical cues are shown to correlate with the expression of A- versus B-type lamins and to direct cell differentiation, the role of different lamin isoforms in cellular mechanotransduction remains unclear. To elucidate the functional relationship between the composition of the nuclear lamina and cell mechanosensitivity, we employ inducible lamin constructs that are expressed in knockout fibroblastic cells. The effects of phosphorylation are studied based on the mobility of lamins and phosphomimetic derivatives in live cells to obtain mechanistic understanding of nuclear mechanosensitivity.