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

Journal article

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.

Authors: He, W; Damianou, A; Vendrell, I; Früh, K; Yin, DI

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences
• Volume: 122
• Issue: 43
• Article number: e2514956122
• Publication date: 2025-10-24
• Acceptance date: 2025-10-02
• DOI: 10.1073/pnas.2514956122
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English