Identification of novel sodium iodide symporter interactors which modulate radioiodine uptake

Patients termed to have radioiodine-refractory differentiated thyroid cancer (RR-DTC) cannot accumulate sufficient radioiodine for a therapeutic response due to sodium iodide symporter (NIS) dysregulation via diminished expression and/or altered plasma membrane localisation. Previous studies identified novel therapeutics to increase NIS expression, but these are associated with poor tolerance and resistance. Meanwhile, regulation of NIS plasma membrane localisation remains poorly defined and, despite protein-protein interactions being well-described to modulate trafficking events, the NIS interactome is limited. Here, two novel functional NIS interactors – ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP) – were identified by mass spectrometry, which positively and negatively modulated radioiodine uptake respectively. In papillary thyroid cancer (PTC), ARF4 is downregulated, and VCP overexpressed, which may provide a putative explanation for repressed NIS function. Subsequent investigations identified co-localisation between ARF4 and NIS at the Golgi as well as co-incident trafficking at the plasma membrane, which led to the hypothesis that ARF4 promotes NIS trafficking to the plasma membrane. In contrast, VCP decreased NIS protein expression, which was suggestive of a role for VCP in NIS processing and degradation. Pharmacological inhibitors Eeyarestatin-1 and NMS-873 overcame VCP inhibition of NIS function, which may highlight a novel therapeutic strategy for RR-DTC