{"doi":"10.1093/genetics/iyae216","title":"TAT-1, a phosphatidylserine flippase, affects molting and regulates membrane trafficking in the epidermis of <i>Caenorhabditis elegans</i>","abstract":"Membrane trafficking is a conserved process required for the import, export, movement, and distribution of proteins and other macromolecules within cells. The Caenorhabditis elegans NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking and are required for the completion of molting. Using a genetic approach, we identified reduction-of-function mutations in tat-1 that suppress nekl-associated molting defects. tat-1 encodes the C. elegans ortholog of mammalian ATP8A1/2, a phosphatidylserine flippase that promotes the asymmetric distribution of phosphatidylserine on the cytosolic leaflet of lipid membrane bilayers. CHAT-1 (human CDC50), a conserved chaperone, was required for the correct localization of TAT-1, and chat-1 inhibition strongly suppressed nekl defects. Using a phosphatidylserine sensor, we found that TAT-1 was required for the normal localization of phosphatidylserine at apical endosomes and that loss of TAT-1 led to aberrant endosomal morphologies. Consistent with these data, TAT-1 localized to early endosomes and to recycling endosomes marked with RME-1, the C. elegans ortholog of the human EPS15 homology domain-containing protein, EHD1. TAT-1, phosphatidylserine biosynthesis, and the phosphatidylserine-binding protein RFIP-2 (human RAB11-FIP2) were all required for the normal localization of RME-1 to apical endosomes. Consistent with these proteins functioning together, inhibition of RFIP-2 or RME-1 led to the partial suppression of nekl molting defects, as did inhibition of phosphatidylserine biosynthesis. We propose that TAT-1 flippase activity, in conjunction with RFIP-2, promotes the recruitment of RME-1 to apical recycling endosomes and that inhibition of TAT-1-RFIP-2-RME-1 can compensate for a reduction in NEKL activities.","journal":"Genetics","year":2024,"id":466948,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":355273,"name":"Philip T. Edeen","orcid":"0000-0002-6247-8259","position":1,"is_corresponding":false},{"id":355275,"name":"David S. Fay","orcid":"0000-0002-7599-4017","position":2,"is_corresponding":false},{"id":1299477,"name":"Shae M. Milne","orcid":null,"position":0,"is_corresponding":true}],"reference_count":118,"raw_metadata":null,"created_at":"2026-07-19T02:05:06.743102Z","pmid":"39722491","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":[]}