Total porteome of liver tumors from mice (p53, MYC driven)

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here we show that immunity-related GTPase family Q protein (IRGQ) acts in the quality control of MHC-I molecules and directs misfolded MHC-I for lysosomal degradation through its binding to GABARAPL2 and LC3B. IRGQ specifically targets the non-conformational heavy chains of MHC-I, sorting them for degradation through the autophagy-lysosome system. In the absence of IRGQ, MHC-I heavy chains accumulate in the cell and partly get localized to the cell surface, thereby increasing interactions with mature MHC-I molecules and promoting immune response. Accordingly, mice suffering from hepatocellular carcinoma with reduced IRGQ levels display higher survival rates and bear more activated CD8+ T cells. Similarly, low IRGQ expression in human liver cancer correlates with higher levels of MHC-I molecules in the tumors, and patient survival is directly affected by IRGQ expression levels in CD8+ enriched tumors. Moreover, human T cells are more reactive toward tumorigenic IRGQ knock-out cells. Thus, we reveal IRGQ as a regulator of MHC-I quality control, mediating tumor immune evasion and marking it as a potential biomarker and therapeutic target.