The sodium iodide symporter (NIS) is required for iodide uptake, which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we used tandem mass spectrometry followed by coimmunoprecipitation and proximity ligation assays to identify and validate two key nodes—ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP)—controlling NIS trafficking. Using cell-surface biotinylation assays and highly inclined and laminated optical sheet microscopy, we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP—a principal component of endoplasmic reticulum (ER)–associated degradation—governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two repurposed FDA-approved VCP inhibitors abrogated VCP-mediated repression of NIS function, resulting in significantly increased NIS at the cell-surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs. Significance: These findings show that ARF4 and VCP are involved in NIS trafficking to the plasma membrane and highlight the possible therapeutic role of VCP inhibitors in enhancing radioiodine effectiveness in radioiodine-refractory thyroid cancer.

中文翻译：

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靶向新型碘化物碘转运体相互作用子ADP-核糖基化因子4和含缬沙星的蛋白增强了放射性碘的摄取。

碘化物摄取需要碘化钠共转运蛋白（NIS），这有助于甲状腺激素的生物合成。NIS已在甲状腺癌的消融放射性碘（RAI）治疗中被开发了75年以上，其转运放射性同位素的能力取决于其在质膜上的定位。在其他恶性肿瘤和疾病模式中，基于NIS的体内成像和治疗诊断策略的出现最近增加了NIS的临床重要性。但是，NIS贩运仍然不明确。在这里，我们使用了串联质谱，然后进行了免疫共沉淀和邻近结扎分析，以识别和验证两个关键节点-ADP-核糖基化因子4（ARF4）和含缬氨酸的蛋白（VCP）-控制NIS交易。使用细胞表面生物素化测定法和高度倾斜的层压光学片显微镜，我们证明了ARF4增强了NIS囊泡从高尔基体到质膜的运输，而VCP是内质网（ER）相关降解的主要成分，是由NIS蛋白水解控制的。基因表达分析表明，VCP表达在侵袭性甲状腺癌和RAI治疗后预后较差的患者中特别诱导。两种经过FDA重新批准的VCP抑制剂废除了VCP介导的NIS功能抑制，导致小鼠和人类甲状腺模型的细胞表面NIS显着增加，RAI摄取显着增加。总的来说，这些发现描绘了NIS的贩运，并突显了使用FDA批准的药物来系统增强RAI治疗的新可能性。意义：这些发现表明ARF4和VCP参与了NIS向质膜的转运，并突显了VCP抑制剂在增强放射性碘难治性甲状腺癌的放射性碘有效性中的可能治疗作用。