Tuberous sclerosis complex (TSC) is caused by mutations of either the TSC1 or TSC2 tumor suppressor gene. TSC causes tumors of the brain, heart, kidney, skin and lymphangioleiomyomatosis (LAM). Here we report that the TSC2 protein physically binds to high-density lipoprotein binding protein (HDLBP), also called vigilin, a core stress granule (SG) protein, and that TSC2 localizes to SGs. SGs contain mRNAs and translation initiation complexes, and regulate gene expression by sequestering specific transcripts, thereby serving a cytoprotective role. TSC2 has never before been shown to localize to SGs and knocking down vigilin impacts SG translocation of TSC2. TSC2-deficient cells showed a striking increase in the number of SGs after thermal shock and arsenite treatment relative to Tsc2-expressing cells. Our findings also show that murine kidney lysates from a model of TSC have increased levels of SG components including G3BP1 and Caprin1. G3BP1 and Caprin are elevated in renal angiomyolipomas (a renal tumor common in patients with TSC) compared with control normal kidney. G3BP1 is also elevated in TSC-associated subependymal giant cell astrocytomas. We found that genetic inhibition of G3BP1 inhibits the proliferation of TSC2-deficient cells in vitro . Finally, in a mouse model of TSC, genetic inhibition of SGs suppresses cell growth, suggesting that targeting SGs may have efficacy in the therapy of TSC. Implications: This study demonstrates that TSC2 physically interacts with HDLBP/vigilin, a component of SGs, that TSC2 localizes to SG and that TSC2-deficient cells have more SGs, suggesting that SGs represent a novel therapeutic target in TSC.

中文翻译：

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TSC2 与 HDLBP/Vigilin 相互作用并调节应力颗粒的形成

结节性硬化症 (TSC) 是由 TSC1 或 TSC2 肿瘤抑制基因的突变引起的。TSC 会导致脑部、心脏、肾脏、皮肤和淋巴管平滑肌瘤病 (LAM) 的肿瘤。在这里，我们报告 TSC2 蛋白与高密度脂蛋白结合蛋白 (HDLBP) 物理结合，也称为 vigilin，一种核心应力颗粒 (SG) 蛋白，并且 TSC2 定位于 SG。SGs 包含 mRNAs 和翻译起始复合物，并通过隔离特定转录物来调节基因表达，从而起到细胞保护作用。TSC2 以前从未被证明可以定位于 SG，并且击倒 vigilin 会影响 TSC2 的 SG 易位。相对于表达 Tsc2 的细胞，TSC2 缺陷细胞在热休克和亚砷酸盐处理后的 SG 数量显着增加。我们的研究结果还表明，来自 TSC 模型的鼠肾裂解物增加了包括 G3BP1 和 Caprin1 在内的 SG 成分水平。与对照正常肾脏相比，肾血管平滑肌脂肪瘤（TSC 患者常见的一种肾肿瘤）中的 G3BP1 和 Caprin 升高。G3BP1 在 TSC 相关的室管膜下巨细胞星形细胞瘤中也升高。我们发现 G3BP1 的遗传抑制在体外抑制了 TSC2 缺陷细胞的增殖。最后，在 TSC 的小鼠模型中，SGs 的基因抑制会抑制细胞生长，这表明靶向 SGs 可能对 TSC 的治疗有效。启示：这项研究表明，TSC2 与 HDLBP/vigilin（SGs 的一种成分）发生物理相互作用，TSC2 定位于 SG，并且 TSC2 缺陷细胞具有更多的 SG，这表明 SG 代表了 TSC 中的新治疗靶点。