KASH proteins transform from passive tethers to dynamic conductors of motor-driven nuclear dynamics.

Nuclear-cytoskeletal coupling orchestrates critical cellular processes from migration to tissue organization. At the core of this machinery, outer nuclear membrane Klarsicht/ANC-1/SYNE homology (KASH) proteins function as sophisticated molecular conductors rather than simple structural tethers. This review examines three principles redefining these versatile proteins: specialized interfaces for selective microtubule motor protein recruitment that orchestrate diverse chromosomal and nuclear dynamics, coordination of multiple cytoskeletal systems through simultaneous engagement with actin and microtubules, and tissue-specific regulation that explains the diverse KASH protein-related disease manifestations. This framework provides insights into conditions from muscular dystrophy to neurodegeneration and suggests targeted therapeutic opportunities.