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

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) evades immune surveillance partly through autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I). 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. A genome-wide CRISPRi screen identified the ER-resident E3 ligase NFXL1 as a mediator of MHC-I ubiquitylation and autophagic capture. Elevated NFXL1 correlates with reduced MHC-I expression and poor patient prognosis, highlighting a targetable pathway regulating PDAC immunogenicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325129 | GEO | 2026/07/22

REPOSITORIES: GEO

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