A cytoplasmic motif in HLA-E that drives clathrin-mediated endocytosis and VCP-associated postendocytic trafficking

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-10-24
DOI
https://doi.org/10.1073/pnas.2514956122
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.00

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article

A cytoplasmic motif in HLA-E that drives clathrin-mediated endocytosis and VCP-associated postendocytic trafficking

Geraldine M. Gillespie, Persephone Borrow, Benedikt Mathias Kessler, Iolanda Vendrell et al.
Proceedings of the National Academy of Sciences
Immune Cell Function and Interaction
article

A cytoplasmic motif in HLA-E that drives clathrin-mediated endocytosis and VCP-associated postendocytic trafficking

Geraldine M. Gillespie, Persephone Borrow, Benedikt Mathias Kessler, Iolanda Vendrell, Daowen I. Yin, Frances M. Brodsky, Simon Brackenridge, Andrew J. McMichael, Wanlin He, Andreas Damianou, Klaus Früh
article en

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.

Proceedings of the National Academy of SciencesVol. 122(43)
Oregon National Primate Research Center (US), Academy of Medical Sciences (GB), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Sichuan University (CN), Discovery Institute (US), Nuffield Orthopaedic Centre (GB), University of Oxford (GB), National Clinical Research (US), Stomatology Hospital (CN), Institute of Structural and Molecular Biology (GB), University College London (GB), Birkbeck, University of London (GB)
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
Openalex Percentile: Top 68%
Immune Cell Function and Interaction
DOIOpen Access PDFOpenAlex
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