A cytoplasmic motif in HLA-E that drives clathrin-mediated endocytosis and VCP-associated postendocytic trafficking
Year: 2025
Type: article
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.
Institutions: Sichuan University, University of Oxford, State Key Laboratory of Oral Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Oregon National Primate Research Center, Oregon Health & Science University, Vaccine and Gene Therapy Institute, Institute of Structural and Molecular Biology, University College London, Birkbeck, University of London
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: Foundation for the National Institutes of Health, Yale University, Washington University in St. Louis, University College London, University of Oxford, National Natural Science Foundation of China, China Scholarship Council, Sichuan University, Chinese Academy of Medical Sciences, National Institutes of Health, Directorate for Biological Sciences, Oregon National Primate Research Center, Biotechnology and Biological Sciences Research Council, West China Hospital, Sichuan University, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W4415523164