Membrane engagement by the HLA-A cytoplasmic tail regulates endocytosis and surface retention

Loss of major histocompatibility complex class I (MHC-I) molecules from the tumor cell surface is a common mechanism of immune evasion; yet, the receptor intrinsic events that initiate their endocytic removal remain unclear. Here, using HLA-A^∗11:01, a human MHC-I heavy chain allotype as a model, we identify a membrane responsive regulatory module within its cytoplasmic tail. The conserved 360-365 segment engages phospholipid membranes and undergoes Cys363-dependent self-association under membrane mimetic conditions, while cooperating with the transmembrane region to shape the molecular proximity of full-length HLA-A. Disruption of this segment weakens association with the trafficking GTPase ARF6, slows receptor internalization, and prolongs HLA-A retention at the cell surface. Consistently, a cell penetrating peptide containing this sequence limits endogenous HLA-A internalization across several tumor cell lines. These findings identify the HLA-A cytoplasmic tail as an active regulator of endocytic trafficking and suggest a strategy for preserving surface HLA-A availability in tumor cells.