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Intracellular pH regulates the ubiquitin-mediated degradation of the atypical MAP kinase ERK3

ABSTRACT: The atypical mitogen-activated protein kinase ERK3 is known for its instability and degradation via the ubiquitin-proteasome system (UPS). However, the specific environmental factors regulating ERK3 turnover have remained unclear. In this study, we demonstrate that intracellular pH (pHi) plays a crucial role in modulating ERK3 stability. We observed that acidification of the extracellular environment significantly increases ERK3 half-life and expression, whereas alkalinization accelerates its degradation. This pH-dependent regulation of ERK3 occurs through the modulation of its ubiquitination by the UPS, with lower pHi reducing ERK3 ubiquitylation and proteasomal degradation. Importantly, this mechanism is consistent across various cell types, highlighting its broad relevance. Moreover, our results suggest that ERK3 stability is not mediated by membrane pH sensors like ASIC1 or TRPV1. Instead, pHi variations directly affect ERK3 stability, likely through protonation-sensitive motifs in its C-terminal region. Furthermore, a proteomic analysis revealed that pH changes globally impact protein stability, including ERK3, suggesting a novel coupling between pH homeostasis and proteome regulation. This study provides critical insights into how pH influences ERK3 turnover and proposes a broader role for pHi in regulating protein stability and cell signaling pathways.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Bonneil

LAB HEAD: Sylvain meloche

PROVIDER: PXD056239 | Pride | 2025-10-07

REPOSITORIES: Pride

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			Action	DRS
	Service_Meloche_2685_PH6_4_230323_350-453_1.mgf	Mgf
	Service_Meloche_2685_PH6_4_230323_350-453_1.raw	Raw
	Service_Meloche_2685_PH6_4_230323_350-453_1.raw.mgf	Mgf
	Service_Meloche_2685_PH6_4_230323_350-453_2.mgf	Mgf
	Service_Meloche_2685_PH6_4_230323_350-453_2.raw	Raw

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Project description:Staphylococcus aureus is a leading cause of hospital- and community-associated infections. The organism’s ability to cause disease can, in part, be attributable to its ability to adapt to otherwise deleterious host-associated stresses. Like other bacterial species, the modulation of mRNA turnover appears to play an important role in S. aureus adaptation to certain environmental stresses. In the current study Affymetrix GeneChips® were used to examine the S. aureus responses to acid and alkaline shock-inducing conditions and to assess whether stress dependent changes in mRNA turnover are likely to facilitate the organism’s ability to tolerate extreme pH challenge. Results indicate that S. aureus adapts to pH shock by eliciting responses expected of organisms coping with pH alteration, including neutralizing cellular internal pH, DNA repair, amino acid biosynthesis and virulence factor expression. Further, it was found that the cellular response to alkaline conditions elicits a transcriptional profile that is similar to that of stringent response induced cells. Consistent with that observation, we show that the activator of the stringent response, (p)ppGpp, levels are profoundly elevated during alkaline shock conditions. We also show that the mRNA turnover properties of acid or alkaline shocked cells significantly differ from that of cells grown at neutral pH. A comparison of the mRNA degradation properties of transcripts whose titers either increased or decreased in response to sudden pH change revealed that alterations in mRNA degradation may, in part, account for the changes in the mRNA levels of factors predicted to mediate pH tolerance. Finally, a set of small stable RNA molecules were induced in response to acid or alkaline shock conditions. As in other organisms, these molecules may mediate mRNA stability and adaptation to otherwise deleterious growth conditions. Staphylococcus aureus strain UAMS-1 was grown to exponential phase and either mock treated (pH maintained at 7.4) or subjected to acid (pH 4)- or alkaline (pH 10) conditions for 30 min. Next, 200 micrograms per ml of rifampicin were added to arrest transcript synthesis. RNA was extracted from cell suspensions at 0, 2.5, 5, 15, and 30 min post-transcriptional arrest, labeled and hybridized to S. aureus GeneChips. A comparison of 0 min samples allowed assessment of acid and alkaline shock responses. A comparison of 0 min to that of various post-transcriptional arrest RNA samples allowed assessment of the mRNA turnover properties of mock vs acid or alkaline shocked cells. Duplicates of each experimental condition and corresponding post-transcriptional arrest time point were used (biological replicates).

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Intracellular pH regulates the ubiquitin-mediated degradation of the atypical MAP kinase ERK3

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