{"doi":"10.1073/pnas.2514956122","title":"A cytoplasmic motif in HLA-E that drives clathrin-mediated endocytosis and VCP-associated postendocytic trafficking","abstract":"Human Leukocyte Antigen E (HLA-E) is a nonclassical MHC class I molecule that exhibits dual immunological functions in regulating natural killer (NK) cells and T cells through unusual trafficking patterns. We previously reported that HLA-E surface expression is low and transient due to its cytoplasmic tail and dominant VL9 peptide, making it a dynamic indicator of cellular status for NK cell surveillance. Here, we identify a sequence motif in the HLA-E cytoplasmic tail that enables rapid internalization via clathrin-mediated endocytosis (CME) through interaction with the adaptor protein 2 (AP-2) complex. Following internalization, HLA-E is routed to endosomes, where the same cytoplasmic motif and peptide loading together facilitate its reappearance on the cell surface-a process influenced by valosin-containing protein (VCP). Our findings reveal previously unrecognized endosomal trafficking pathways and regulatory mechanisms that distinguish HLA-E from classical HLA class I molecules, with broad implications for understanding the immunoregulatory roles of HLA-E.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":527301,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"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":1403986,"name":"Andreas Damianou","orcid":"0000-0001-9383-5100","position":1,"is_corresponding":false},{"id":1222604,"name":"Iolanda Vendrell","orcid":"0000-0001-7187-4061","position":2,"is_corresponding":false},{"id":474083,"name":"Klaus Früh","orcid":null,"position":3,"is_corresponding":false},{"id":1403987,"name":"Daowen I. Yin","orcid":"0009-0002-3774-8533","position":4,"is_corresponding":false},{"id":1403988,"name":"Frances M. Brodsky","orcid":"0000-0002-1334-9258","position":5,"is_corresponding":false},{"id":106103,"name":"Benedikt M. Kessler","orcid":"0000-0002-8160-2446","position":6,"is_corresponding":false},{"id":447715,"name":"Simon Brackenridge","orcid":"0000-0002-0587-7560","position":7,"is_corresponding":false},{"id":269955,"name":"Persephone Borrow","orcid":"0000-0002-3877-9780","position":8,"is_corresponding":false},{"id":447717,"name":"Geraldine M. Gillespie","orcid":"0000-0002-1075-870X","position":9,"is_corresponding":false},{"id":106118,"name":"Andrew J. McMichael","orcid":"0000-0002-9101-7478","position":10,"is_corresponding":false},{"id":1033485,"name":"Wanlin He","orcid":"0000-0002-8117-9692","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41134633","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":[]}