Scerra, Gianluca (2023) A suboptimal signal peptide defines spatiotemporal control of PD-L1 expression. [Tesi di dottorato]

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Malignant cells exploit the expression of the programmed death-1 (PD-1)-ligand 1 (PD-L1) to avoid T-cell-mediated immunosurveillance and promote tumor survival and expansion. Post-translational modifications have emerged as important regulatory mechanisms to modulate PD-L1 expression on the cell surface of cancer cells. However, spatiotemporal control of such modifications is still poorly understood. Here we show that amino-terminal signal peptide plays a major role in dictating the right temporal window for post-translational modifications. Particularly, we have developed the cytosolic version of the retention using selective hook assay (cytoRUSH) to demonstrate that the signal peptide of PD-L1 is suboptimal for the endoplasmic reticulum translocation and introduces a lagging time for pre-translocational modifications acquisition. Accordingly, PD-L1 equipped with an optimized signal peptide variant was insensitive to AMPK-dependent post-translational modifications relevant for driving PD-L1 down-modulation by the proteasome. Moreover, this variant renders PD-L1 defective in trafficking, maturation, and localization to the plasma membrane thereby confirming the physiological relevance of the lagging time introduced by its own signal peptide. In conclusion, these findings suggest that a less efficient kinetic of translocation into the endoplasmic reticulum represents the key step for PD-L1 protein modulation by post-translational modifications acquisition and open intriguing future perspectives for pharmacological applications based on PD-L1 signal peptide targeting in cancer therapy.

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