{"doi":"10.1016/j.cub.2025.08.025","title":"The KASH protein UNC-83 differentially regulates kinesin-1 activity to control developmental stage-specific nuclear migration","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 differential isoform-dependent mechanism for developmental regulation of nuclear migration directionality. The nuclear envelope Klarsicht/ANC-1/Syne homology (KASH) protein UNC-83 in Caenorhabditis elegans exists in multiple isoforms that differentially control motor activity to achieve tissue-specific nuclear positioning. 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 the UNC-83a-specific N-terminal domain functions as a kinesin-1 inhibitory module by directly binding the kinesin heavy chain (UNC-116). This interaction prevents kinesin-1 activation and reduces the protein's affinity for kinesin light chain (KLC-2), allowing for dynein-mediated transport. By contrast, UNC-83c exhibits high-affinity binding to KLC-2, promoting kinesin-1 activation for plus-end-directed movement. AlphaFold structural predictions reveal that UNC-83 contains five spectrin-like repeats, with two located within the inhibitory N-terminal domain. Genetic analysis demonstrates that these spectrin-like repeats are essential for dynein-dependent P cell nuclear migration but dispensable for kinesin-1-dependent hyp7 migration. This isoform-specific inhibition, combined with differential affinity for KLC-2, establishes a mechanism for achieving directional control of nuclear positioning during development. Together, these interdisciplinary studies reveal how alternative isoforms of cargo adaptors can generate developmental stage-specific regulation of motor activity.","journal":"Current Biology","year":2025,"id":542260,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9492,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":328385,"name":"Natalie Sahabandu","orcid":"0009-0005-0129-2564","position":1,"is_corresponding":false},{"id":552272,"name":"Daniel Elnatan","orcid":"0000-0002-8359-0522","position":2,"is_corresponding":false},{"id":579406,"name":"Ellen F. Gregory","orcid":"0000-0002-2228-8258","position":3,"is_corresponding":false},{"id":525613,"name":"Kyoko Chiba","orcid":"0000-0001-6919-2782","position":4,"is_corresponding":false},{"id":252458,"name":"Shinsuke Niwa","orcid":"0000-0002-8367-9228","position":5,"is_corresponding":false},{"id":428821,"name":"G. W. Gant Luxton","orcid":"0000-0002-6180-8906","position":6,"is_corresponding":false},{"id":202406,"name":"Richard J. McKenney","orcid":"0000-0002-8423-0852","position":7,"is_corresponding":false},{"id":533196,"name":"Daniel A. Starr","orcid":"0000-0001-7339-6606","position":8,"is_corresponding":false},{"id":1131497,"name":"Selin Gümüşderelioğlu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T02:52:55.809501Z","pmid":"40925371","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}