The truncated cytoplasmic tail of HLA-G serves a quality-control function in post-ER compartments

In contrast to the current model of MHC class I trafficking, which predicts that once a MHC class I molecule leaves the ER, it moves to the cell surfa ce by bulk flow, we show that HLA-G that is loaded with suboptimal peptides is retrieved from post-ER compartments to the ER. Loading of HLA-G with hi gh-affinity peptides abrogates this retrieval due to the lack of binding af finity to coatomer. Moreover, the loss of the endocytosis motif in the trun cated cytoplasmic tail results in the prolonged half-life of HLA-G on the c ell surface. Our findings reveal that surface expression of HLA-G can be fu rther regulated in post-ER compartments and that the truncated cytoplasmic tail plays a critical role in such quality-control mechanisms.