{"doi":"10.1093/genetics/iyae076","title":"Notch signaling without the APH-2/nicastrin subunit of gamma secretase in <i>Caenorhabditis elegans</i> germline stem cells","abstract":"The final step in Notch signaling activation is the transmembrane cleavage of Notch receptor by γ secretase. Thus far, genetic and biochemical evidence indicates that four subunits are essential for γ secretase activity in vivo: presenilin (the catalytic core), APH-1, PEN-2, and APH-2/nicastrin. Although some γ secretase activity has been detected in APH-2/nicastrin-deficient mammalian cell lines, the lack of biological relevance for this activity has left the quaternary γ secretase model unchallenged. Here, we provide the first example of in vivo Notch signal transduction without APH-2/nicastrin. The surprising dispensability of APH-2/nicastrin is observed in Caenorhabditis elegans germline stem cells (GSCs) and contrasts with its essential role in previously described C. elegans Notch signaling events. Depletion of GLP-1/Notch, presenilin, APH-1, or PEN-2 causes a striking loss of GSCs. In contrast, aph-2/nicastrin mutants maintain GSCs and exhibit robust and localized expression of the downstream Notch target sygl-1. Interestingly, APH-2/nicastrin is normally expressed in GSCs and becomes essential under conditions of compromised Notch function. Further insight is provided by reconstituting the C. elegans γ secretase complex in yeast, where we find that APH-2/nicastrin increases but is not essential for γ secretase activity. Together, our results are most consistent with a revised model of γ secretase in which the APH-2/nicastrin subunit has a modulatory, rather than obligatory role. We propose that a trimeric presenilin-APH-1-PEN-2 γ secretase complex can provide a low level of γ secretase activity, and that cellular context determines whether or not APH-2/nicastrin is essential for effective Notch signal transduction.","journal":"Genetics","year":2024,"id":497400,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"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":437742,"name":"Karen C. Smith","orcid":"0000-0003-0330-1610","position":1,"is_corresponding":false},{"id":857599,"name":"Emma C. Fink","orcid":"0000-0002-6589-8558","position":2,"is_corresponding":false},{"id":1344388,"name":"Woohyun Kwen","orcid":null,"position":3,"is_corresponding":false},{"id":1344389,"name":"Nina Yoo","orcid":null,"position":4,"is_corresponding":false},{"id":1344147,"name":"Zachary J. West","orcid":"0000-0001-7671-9781","position":5,"is_corresponding":false},{"id":654197,"name":"Nora L. Sullivan","orcid":null,"position":6,"is_corresponding":false},{"id":1344390,"name":"Alex S Farthing","orcid":null,"position":7,"is_corresponding":false},{"id":1344148,"name":"Valerie A. Hale","orcid":"0000-0002-5727-928X","position":8,"is_corresponding":false},{"id":1344149,"name":"Caroline Goutte","orcid":"0000-0001-6067-5999","position":9,"is_corresponding":false},{"id":1278095,"name":"David M. Brinkley","orcid":"0000-0002-6472-9330","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T02:09:34.764412Z","pmid":"38717968","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":[]}