Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
PLoS One. 2013 Aug 15;8(8):e71294. doi: 10.1371/journal.pone.0071294. eCollection 2013.
Acetic acid-induced apoptosis in yeast is accompanied by an impairment of the general protein synthesis machinery, yet paradoxically also by the up-regulation of the two isoforms of the heat shock protein 90 (HSP90) chaperone family, Hsc82p and Hsp82p. Herein, we show that impairment of cap-dependent translation initiation induced by acetic acid is caused by the phosphorylation and inactivation of eIF2α by Gcn2p kinase. A microarray analysis of polysome-associated mRNAs engaged in translation in acetic acid challenged cells further revealed that HSP90 mRNAs are over-represented in this polysome fraction suggesting preferential translation of HSP90 upon acetic acid treatment. The relevance of HSP90 isoform translation during programmed cell death (PCD) was unveiled using genetic and pharmacological abrogation of HSP90, which suggests opposing roles for HSP90 isoforms in cell survival and death. Hsc82p appears to promote survival and its deletion leads to necrotic cell death, while Hsp82p is a pro-death molecule involved in acetic acid-induced apoptosis. Therefore, HSP90 isoforms have distinct roles in the control of cell fate during PCD and their selective translation regulates cellular response to acetic acid stress.
乙酸诱导酵母细胞凋亡伴随着一般蛋白质合成机制的损伤，但矛盾的是，也伴随着热休克蛋白 90（HSP90）伴侣家族的两种同工型 Hsc82p 和 Hsp82p 的上调。在此，我们表明，乙酸诱导的帽依赖性翻译起始受损是由 Gcn2p 激酶磷酸化和失活 eIF2α 引起的。在乙酸处理的细胞中进行的翻译相关多核糖体相关 mRNA 的微阵列分析进一步表明，HSP90 mRNA 在该多核糖体部分中过度表达，提示 HSP90 在乙酸处理时优先翻译。使用 HSP90 的遗传和药理学阻断来揭示 HSP90 同工型翻译在程序性细胞死亡（PCD）中的相关性，这表明 HSP90 同工型在细胞存活和死亡中具有相反的作用。Hsc82p 似乎促进存活，其缺失导致坏死性细胞死亡，而 Hsp82p 是参与乙酸诱导凋亡的促死亡分子。因此，HSP90 同工型在 PCD 期间控制细胞命运中具有不同的作用，其选择性翻译调节细胞对乙酸应激的反应。
