A gene expression correlation analysis of cell mechanosensitive systems identifies DANGER as a nuclear mechanoresponsive protein

Cellular mechanoadaptation is a complex process involving multiple mechanotransduction pathways and mechanisms that operate in different cellular locations and organelles. Despite recent advances, the identity of all components and the molecular mechanisms of these pathways remain poorly understood. Here, we describe a strategy to identify previously unrecognized mechanotransduction components throughout the cell. Using this approach, we identify several candidate proteins involved in mechanotransduction in cellular organelles. A screen of selected candidates identified DANGER as a nuclear envelope component required for nuclear mechanoadaptation and stability. DANGER is distributed in discrete regions of the nuclear envelope. Notably, DANGER is highly enriched in bent and stretched regions of the nuclear envelope, a feature not observed for other nuclear envelope proteins associated with mechanotransduction pathways. Upon increased nuclear tension, either induced by osmotic swelling or integrin-mediated nuclear deformation, DANGER responds by forming larger clusters, suggesting that DANGER can sense changes in the nuclear envelope induced by mechanical cues. Furthermore, DANGER-depleted nuclei have a larger area, are more elongated, and are more prone to forming blebs, consistent with DANGER localizing to regions under higher tension. Together, these findings identify DANGER as a key nuclear envelope component regulating nuclear shape and nuclear envelope stability, and provide proof of concept that our gene expression correlation-based strategy can identify previously unrecognized mechanotransduction components.