Acetic Acid Causes Endoplasmic Reticulum Stress and Induces the Unfolded Protein Response in Saccharomyces cerevisiae

Abstract

Since acetic acid inhibits the growth and fermentation ability of Saccharomyces cerevisiae, it is one of the practical hindrances to the efficient production of bioethanol from a lignocellulosic biomass. Although extensive information is available on yeast response to acetic acid stress, the involvement of endoplasmic reticulum (ER) and unfolded protein response (UPR) has not been addressed. We herein demonstrated that acetic acid causes ER stress and induces the UPR. The accumulation of misfolded proteins in the ER and activation of Ire1p and Hac1p, an ER-stress sensor and ER stress-responsive transcription factor, respectively, were induced by a treatment with acetic acid stress (>0.2% v/v). Other monocarboxylic acids such as propionic acid and sorbic acid, but not lactic acid, also induced the UPR. Additionally, ire1Δ and hac1Δ cells were more sensitive to acetic acid than wild-type cells, indicating that activation of the Ire1p-Hac1p pathway is required for maximum tolerance to acetic acid. Furthermore, the combination of mild acetic acid stress (0.1% acetic acid) and mild ethanol stress (5% ethanol) induced the UPR, whereas neither mild ethanol stress nor mild acetic acid stress individually activated Ire1p, suggesting that ER stress is easily induced in yeast cells during the fermentation process of lignocellulosic hydrolysates. It was possible to avoid the induction of ER stress caused by acetic acid and the combined stress by adjusting extracellular pH.

The VFH1 (YLL056C) promoter is vanillin‐inducible and enables mRNA translation despite pronounced translation repression caused by severe vanillin stress in Saccharomyces cerevisiae

“…We examined two conditions for each stress (except for glucose starvation), namely, mild stress condition and severe stress condition. The mild stress conditions (0.1% acetic acid, 8% ethanol, heat shock at 37°C, and 0.4 m m H 2 O 2 ) activate various stress‐responsive transcriptional factors and inhibit yeast growth, whereas the severe stress conditions (0.2% acetic acid, 10% ethanol, heat shock at 42°C and 1.0 m m H 2 O 2 ) cause serious effects on yeast including cell death (Figley, Bieri, Kolaitis, et al, ; Izawa, Kita, Ikeda, et al, ; Kawazoe, Kimata, & Izawa, ; Mariani, Mathias, da Silva, et al, ; Narendranath, Thomas, & Ingledew, ; Nguyen et al, ; Yamamoto & Izawa, ; Yamauchi & Izawa, ). It has been reported that heat shock activates the transcription of YLL056C (Wu & Li, ).…”

“…serious effects on yeast including cell death (Figley, Bieri, Kolaitis, et al, 2014;Izawa, Kita, Ikeda, et al, 2008;Kawazoe, Kimata, & Izawa, 2017;Mariani, Mathias, da Silva, et al, 2008;Narendranath, Thomas, & Ingledew, 2001;Nguyen et al, 2014;Yamauchi & Izawa, 2016). It has been reported that heat shock activates the transcription of YLL056C (Wu & Li, 2008).…”

Translation Control of HAC1 by Regulation of Splicing in Saccharomyces cerevisiae

“…Many factors contribute to protein unfolding and misfolding. These include overexpression of an exogenous protein, e.g., a mouse protein in yeast cells [76], disruption of O-mannosylation in yeast [77], imbalance of ion concentrations such as calcium [78] and cadmium [79], excess of acetic acid, propionic acid and sorbic acid [80], antifungal agents that perturb protein folding such as monoterpene carvacrol [81,82], tunicamycin [18], dithiothreitol [83,84,85], hypoxia [86], or acidosis [67].…”

The unfolded protein response of yeast <i>Saccharomyces cerevisiae</i> and other organisms

“…Miyagawa et al (2014) reported that culturing cells under high-ethanol conditions causes protein denaturation and aggregation, which activate Ire1. Moreover, acetic acid, a byproduct of bioethanol production from lignocellulosic biomass, is reported to be an ER stressor (Kawazoe et al 2017). The environmental pollutant cadmium also activates Ire1 through impairment of protein folding in S. cerevisae ER (Le et al 2016).…”