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

TL;DR

This study reveals how cancer cells avoid immune detection by altering MHC-I expression through a complex signaling pathway involving GLDC and FBXL3.

Contribution

The novel contribution is identifying the SRC-FBXL3-GLDC-MHC-I regulatory circuit that mediates immune evasion in tumors.

Findings

GLDC is polyubiquitinated at K636 following EGFR activation.

SRC-mediated FBXL3 phosphorylation at Y306 enables interaction with GLDC to suppress MHC-I expression.

Phosphorylation of FBXL3Y306 inhibits CD8+ T cell immunity in tumors.

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 GLDCK636 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 FBXL3Y306 decreases MHC-I levels in tumor cells and inhibits CD8+ T cells immunity in tumors. Consistently, inhibitors of SRC improves tumor-specific CD8+ T cells functions in TME and sensitizes antitumor effects of anti-PD-1 therapy. Our findings reveal an SRC-FBXL3-GLDC-MHC-I regulatory circuit that underlies CD8+ T cells immune evasion, and provide a potential therapeutic target to enhance ICB therapy.

Image 1

•GLDC is polyubiquitinated at K636 following EGFR activation.•EGFR activation triggers SRC-mediated FBXL3 phosphorylation at Y306.•Phosphorylation of FBXL3Y306 targets GLDCK636 for K63-linked polyubiquitination.•GLDCK636 polyubiquitination and FBXL3Y306 phosphorylation decrease MHC-I levels and inhibit CD8+ T cells immunity in tumors.

GLDC is polyubiquitinated at K636 following EGFR activation.

EGFR activation triggers SRC-mediated FBXL3 phosphorylation at Y306.

Phosphorylation of FBXL3Y306 targets GLDCK636 for K63-linked polyubiquitination.

GLDCK636 polyubiquitination and FBXL3Y306 phosphorylation decrease MHC-I levels and inhibit CD8+ T cells immunity in tumors.

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