Mechanical regulation of LINC complex function: structural basis, physiological roles, and disease mechanisms in...

How mechanical stimuli cross the nuclear envelope and are converted into nuclear structural and transcriptional responses is a central question in understanding cellular mechanical adaptation and its failure. The LINC complex is composed of inner nuclear membrane SUN proteins and outer nuclear membrane KASH/Nesprin proteins, and establishes a continuous transnuclear mechanical pathway through its connections with the nuclear lamina and the cytoskeleton. Current evidence indicates that the LINC complex is not a passive molecular bridge. Instead, through SUN-KASH pairing, Nesprin isoforms and perinuclear cytoskeletal linkages, it selects and distributes mechanical inputs from different sources, thereby regulating nuclear positioning, nuclear prestress, nuclear pore transport, chromatin organization and mechanosensitive transcriptional programs. These mechanisms participate in development and in the mechanical adaptation of skeletal and cardiac muscle. When disrupted, they may manifest as global mechanical uncoupling, local stress overload and imbalanced nuclear responses, and are associated with pathological processes including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, neurological disease, premature ageing and tumour invasion. On the basis of this evidence, we propose a continuous framework of "mechanical input selection, transmembrane force distribution, nuclear response conversion and tissue outcome" to explain tissue selectivity and phenotypic heterogeneity in LINC-related diseases, and to inform patient variant assessment, disease stratification and precise intervention in aberrant force-transmission pathways.