一價金屬鉈抑制核醣體生合成進而影響蛋白質生成

Abstract

鉈 ( Thallium, Tl ) 為 3A 族之稀有金屬元素，多以一價 ( Tl(I) ) 或三價 ( Tl(III) ) 的形式在環境中廣泛分佈。因為可應用於超導體合金，於高科技產業上的需求與日間進，而被認為是新興的汙染物。鉈影響許多的代謝途徑，且對於生物具有高毒性。因此我們分析鉈如何影響細胞的生理功能。在研究中發現，處於鉈毒性之細胞有 eIF2α 磷酸化現象，以及蛋白質合成量減少的趨勢，曾有研究提到，鉈會和蛋白質上的硫醇基 ( -SH ) 結合而抑制蛋白質功能。雖然大量累積變性蛋白會活化內質網壓力，但在我們的實驗條件下卻無觀察到。值得注意的，研究中發現核醣體的60S 次單元與40S 次單元比例，隨著鉈濃度的增加而下降。因為Tl+和鉀離子擁有相似電性及離子半徑，曾有研究說鉈會取代核醣體上鉀的結合位而抑制核醣體的活性。但是，經由自噬作用或蛋白酶體降解核醣體的情形並沒有被觀察到。有趣的是，鉈處理後，RNA 聚合酶 I 的活性沒有改變，但 rRNA 的成熟過程則出現嚴重缺失；核仁蛋白的細胞位置改變且累積量下降。因此，我們提出鉈降低蛋白質合成率的機制，主要是導致不正長的核醣體生成，進而造成細胞生長停止及死亡。

Thallium is a metal classified in the group III A, distributed in the environment as monovalent Tl(I) and trivalent Tl(III) state. Thallium is considered as an emergent contamination because of its potential use in superconducting alloys, with increasing demand from high-technology industry. Tl(I) is highly toxic to the animals since it can affect numerous metabolic processes. We dissect how Tl(I) impacts physiological functions of the cells. We observed that protein synthesis was highly decreased and eIF2α was phosphorylated after thallium treatment. It has been proposed that Tl(I) can interact with sulfhydryl groups to inactivate the protein functions. Although accumulation of denature proteins would activate ER stress, it was not observed in our experimental conditions. Notably, the ratio of ribosomal large subunit (60S) to small subunit (40S) was decreased with increasing amount of thallium. Due to Tl(I) shares similarities with potassium (K) in ionic charge and atomic radius, it has been proposed that Tl(I) occupies certain K+-binding sites and inactivates ribosome function. Thallium may impact 60S levels from triggering degradation of inactive 60S. However, activation of autophagy or proteasomal degradation of large subunits was not observed. Interestingly, while the activity of RNA polymerase I was not altered, rRNA processing was severely blocked after Tl(I) treatment. In addition, nucleolar proteins mislocalized in the cells and under-accumulated. Therefore, we proposed that Tl(I) decreased protein synthesis from abnormal ribosome synthesis, resulting cell growth inhibition and lethality.