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A novel role for pH in protein regulation
Published on November 18, 2025
The team led by Sylvain Meloche, Director of IRIC’s Signalling and Cell Growth Research Unit, has discovered a new mechanism for the global regulation of proteins by intracellular pH. The study, co-led by PhD students Chloé Tesnière and Fadia Boudghene-Stambouli, has been published in the journal PNAS. The teams led by Pierre Thibault, Director of IRIC’s Proteomics and Mass Spectrometry Research Unit, and Laurent Counillon, Director of the Molecular Physio-Medicine Laboratory at CNRS-Université Côte d’Azur (Nice, France), also contributed to the project.
A switch for ERK3 stability
ERK3 is a protein of the MAPK signalling pathway that promotes tumor development. It remains a mystery in many ways: its functions are not clearly understood and it is much more unstable than other similar proteins. The Meloche lab sought to identify the environmental factors that cause ERK3 to be degraded by cellular machinery.
The team discovered that intracellular pH regulates ERK3 stability in a very precise and reversible manner: acidification of the cell stabilizes it, while alkalization causes its degradation.
These results provide new insights into the study of ERK3 in pathological contexts, particularly when there are variations in intracellular pH. For example, ERK3 levels could increase in certain regions of solid tumors, where the cellular environment is hypoxic and acidic. This stabilization of ERK3 could be a mechanism by which tumor cells adapt to their acidic environment, promoting their survival.
A fundamental mechanism with a global effect
The researchers also found that pH fluctuations affect many proteins in the cell, not just ERK3. Since pH regulation is a mechanism conserved in all species, these results point to a global role for pH in regulating protein stability, a role that was previously unsuspected.
The work of the Meloche laboratory thus paves the way for the integration of pH as a regulator of proteins and cellular signaling pathways, including in response to stress and in pathological contexts.
Cited study
Tesnière C, Boudghene-Stambouli F, Severin M, Poët M, Voisin L, Ponniah M, Pascariu M, Bonneil E, Trempe JF, Thibault P, Counillon L, Pedersen SF, Meloche S. Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3. Proc Natl Acad Sci U S A. 2025 Oct 28;122(43):e2501825122. doi: 10.1073/pnas.2501825122. Epub 2025 Oct 22. PMID: 41123996; PMCID: PMC12582255.
