DDX3 regulates cancer immune surveillance via 3' UTR-mediated cell-surface expression of PD-L1
CELL REPORTS(2024)
摘要
Programmed death -1 (PD-1)/PD ligand-1 (PD -L1) -mediated immune escape contributes to cancer development and has been targeted as an anti -cancer strategy. Here, we show that inhibition of the RNA helicase DDX3 increased CD8 + T cell infiltration in syngeneic oral squamous cell carcinoma tumors. DDX3 knockdown compromised interferon -g -induced PD -L1 expression and, in particular, reduced the level of cell -surface PD -L1. DDX3 promoted surface PD -L1 expression by recruiting the adaptor protein 2 (AP2) complex to the 3 ' UTR of PD -L1 mRNA. DDX3 depletion or 3 ' UTR truncation increased the binding of the coatomer protein complexes to PD -L1, leading to its intracellular accumulation. Therefore, this 3 ' UTR-dependent mechanism may counteract cellular negative effects on surface trafficking of PD -L1. Finally, pharmaceutic disruption of DDX3's interaction with AP2 reduced surface PD -L1 expression, supporting that the DDX3-AP2 pathway routes PD -L1 to the cell surface. Targeting DDX3 to modulate surface trafficking of immune checkpoint proteins may provide a potential strategy for cancer immunotherapy.
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关键词
3’ UTR-mediated protein-protein interaction,YXXØ,sorting motif
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