Abstract
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.
Highlights
Yeast cells respond to stress in multiple ways ranging from activation of pathways that promote survival to those eliciting programmed cell death (PCD)
Our previous work has shown that acetic acidinduced apoptosis in yeast cells is characterized by the impairment of general protein synthesis, yet it is paradoxically associated with the up-regulation of the two isoforms of the heat shock protein 90 (HSP90) [4]
We have previously shown that induction of apoptosis by acetic acid in yeast cells results in severe attenuation of translation [4]
Summary
Yeast cells respond to stress in multiple ways ranging from activation of pathways that promote survival to those eliciting programmed cell death (PCD). Our previous work has shown that acetic acidinduced apoptosis in yeast cells is characterized by the impairment of general protein synthesis, yet it is paradoxically associated with the up-regulation of the two isoforms of the heat shock protein 90 (HSP90) [4]. The different HSP90 isoforms, their selective post-translational modifications and client proteins could explain the dual role of HSP90 in cell survival and death. Among the different HSP90 functions, these chaperones are involved in yeast translational control [17,18] and necrotic cell death [12,19]. The translation control of HSP90 mRNAs and their impact on yeast cell death has not yet been addressed
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