The KASH protein UNC-83 differentially regulates kinesin-1 activity to control developmental stage-specific nuclear migration

Gümüsderelioglu, S.; Sahabandu, N.; Elnatan, D.; Gregory, E. F.; Chiba, K.; Niwa, S.; Luxton, G. G.; McKenney, R. J.; Starr, D. A.

doi:10.1101/2025.03.06.641899

bioRxiv · 10.1101/2025.03.06.641899

The KASH protein UNC-83 differentially regulates kinesin-1 activity to control developmental stage-specific nuclear migration

Gümüsderelioglu, S.·Sahabandu, N.·Elnatan, D.·Gregory, E. F.·Chiba, K.·Niwa, S.·Luxton, G. G.·McKenney, R. J.·Starr, D. A.

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Abstract

Nuclear migration plays a fundamental role in development, requiring precise spatiotemporal control of bidirectional movement through dynein and kinesin motors. Here, we uncover a mechanism for developmental regulation of nuclear migration directionality. The nuclear envelope KASH protein UNC-83 in Caenorhabditis elegans exists in multiple isoforms that differentially control motor activity. The shorter UNC-83c isoform promotes kinesin-1-dependent nuclear movement in embryonic hyp7 precursors, while longer UNC-83a/b isoforms facilitate dynein-mediated nuclear migration in larval P cells. We demonstrate that UNC-83as N-terminal domain functions as a kinesin-1 inhibitory module by directly binding kinesin heavy chain (UNC-116). This isoform-specific inhibition, combined with differential affinity for kinesin light chain (KLC-2), establishes a molecular switch for directional control. Together, these interdisciplinary studies reveal how alternative isoforms of cargo adaptors can generate developmental stage-specific regulation of motor activity during development.

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Gümüsderelioglu, S., Sahabandu, N., Elnatan, D., Gregory, E. F., Chiba, K., Niwa, S., Luxton, G. G., McKenney, R. J., Starr, D. A.. 2025-03-07. The KASH protein UNC-83 differentially regulates kinesin-1 activity to control developmental stage-specific nuclear migration. https://doi.org/10.1101/2025.03.06.641899

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