A multi-subunit capture complex facilitates degradation of ER stalled MHC-I in pancreatic cancer

However, the basis for this susceptibility remains unclear. Using synchronized ER exit assays, we show that PDAC cells retain MHC-I in the endoplasmic reticulum and inefficiently traffic it to the plasma membrane.

An autophagic capture complex composed of the ER-phagy receptor TEX264 and the cargo receptor NBR1 mediates targeting of MHC-I for lysosomal degradation. Suppression of either receptor restores MHC-I levels and increases surface presentation. Binding of MHC-I to the capture complex is linked to antigen presentation efficiency as inhibition of antigen loading enhances MHC-I binding to the TEX264–NBR1 complex, whereas expression of high-affinity ER-targeted peptides reduces binding and promotes surface localization.