biostudies-literatureSahabandu NNIGMS NIH HHSeadq4726https://www.ebi.ac.uk/biostudies/studies/S-EPMC11844729biostudies-literatureUnknown11(8)Nesprin-2 Giant (N2G) is a large integral membrane protein that physically connects the nucleus to the cytoskeleton, but how N2G performs this activity to maintain nuclear positioning and drive nuclear movement is unclear. This study investigates N2G's role in nucleocytoskeletal coupling, a process critical for cellular function and development. We uncover multiple roles for N2G, including its activity as an F-actin bundler, an adapter that activates kinesin-1 motors, and a mediator of cytoskeletal cross-talk. Notably, N2G directly links kinesin-1 to F-actin, enabling the transport of actin filaments along microtubule tracks, establishing active cross-talk between the actin and microtubule cytoskeletons. These findings provide crucial insights into nuclear movement, advancing our understanding of fundamental cellular processes and their implications in development and disease.Science advancesActive microtubule-actin cross-talk mediated by a nesprin-2G-kinesin complex.PMC11844729R35 GM133688R35 GM124889R35 GM134859Okada KStarr DASahabandu NKhan AOri-McKenney KMMcKenney RJLuxton GWElnatan DfalseActive microtubule-actin cross-talk mediated by a nesprin-2G-kinesin complex.Nesprin-2 Giant (N2G) is a large integral membrane protein that physically connects the nucleus to the cytoskeleton, but how N2G performs this activity to maintain nuclear positioning and drive nuclear movement is unclear. This study investigates N2G's role in nucleocytoskeletal coupling, a process critical for cellular function and development. We uncover multiple roles for N2G, including its activity as an F-actin bundler, an adapter that activates kinesin-1 motors, and a mediator of cytoskeletal cross-talk. Notably, N2G directly links kinesin-1 to F-actin, enabling the transport of actin filaments along microtubule tracks, establishing active cross-talk between the actin and microtubule cytoskeletons. These findings provide crucial insights into nuclear movement, advancing our understanding of fundamental cellular processes and their implications in development and disease.2025-01-01T00:00:00Z2025 Feb2026-04-08T19:55:09.335Z2025-04-06T22:41:08.166ZS-EPMC118447293998299810.1126/sciadv.adq4726