Phosphorylation of FBXL3 mediates GLDC polyubiquitination to suppress MHC-I expression and promote cancer immune evasion.

ABSTRACT: Glycine decarboxylase (GLDC) is overexpressed in multiple tumor types and contributes to tumorigenesis or immune evasion by unclarified mechanisms. Here we report that GLDC is polyubiquitinated at K636 following EGFR activation, which drives GLDC-dependent transcriptional inhibition of MHC-I genes and induces tumor cells to evade CD8⁺ T cell-mediated immunosurveillance. Mechanistically, EGFR activation triggers SRC-mediated FBXL3 phosphorylation at Y306, enabling its interaction with GLDC in nucleus. FBXL3 targets GLDC^K636 for K63-linked polyubiquitination, and promotes the interaction of GLDC with SMARCE1/DMAP1 to inhibit STAT1-triggered transcriptional activation, resulting in transcriptional inhibition of downstream MHC-I genes. Phosphorylation of FBXL3^Y306

SUBMITTER: Liu R 

PROVIDER: S-EPMC12924200 | biostudies-literature | 2026 Apr

REPOSITORIES: biostudies-literature