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

## TL;DR

The paper identifies a specific motif in HLA-E that controls its rapid cell surface turnover and trafficking, offering new insights for immunotherapy.

## Contribution

Discovery of a lysine/tryptophan-based motif in HLA-E that drives clathrin-mediated endocytosis and postendocytic trafficking.

## Key findings

- HLA-E's cytoplasmic motif enables rapid internalization via clathrin-mediated endocytosis.
- HLA-E's surface reappearance is regulated by VCP and depends on peptide binding.
- The motif and trafficking mechanism distinguish HLA-E from classical MHC class I molecules.

## Abstract

By presenting a conserved self-peptide to NKG2A/C-CD94 receptors on NK cells, nonpolymorphic HLA-E plays a central role in regulating innate immunity. While HLA-E can also present foreign peptides to stimulate protective T cell responses, these are naturally rare and subdominant to classical T cell responses. Here, we identify a lysine/tryptophan-based motif in the HLA-E cytoplasmic tail that facilitates rapid surface turnover via clathrin-mediated endocytosis. This motif, combined with peptide binding, supports rapid surface reappearance of HLA-E, a process modulated by the AAA ATPase VCP. These insights into the cell biology of HLA-E open broad avenues for enhancing these noncanonical T cell responses, offering promising opportunities for universal immunotherapies.

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.