2. Academic Validation
  3. Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3

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.
Chloé Tesnière # 1 2,  Fadia Boudghene-Stambouli # 1 3,  Marc Severin 4,  Mallorie Poët 5,  Laure Voisin 1,  Muthulakshmi Ponniah 4,  Mirela Pascariu 1,  Eric Bonneil 1,  Jean-François Trempe 6 7,  Pierre Thibault 1 8,  Laurent Counillon 5,  Stine Falsig Pedersen 4,  Sylvain Meloche 1 2 3
Affiliations

Affiliations

  • 1 Institute for Research in Immunology and Cancer, Montreal, QC H3T 1J4, Canada.
  • 2 Molecular Biology Program, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
  • 3 Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
  • 4 Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen DK-2200, Denmark.
  • 5 CNRS, Laboratoire de Physiomédecine Moléculaire, Université Côte d'Azur, Nice 06107, France.
  • 6 Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada.
  • 7 Centre de Recherche en Biologie Structurale, McGill University, Montreal, QC H3G 1Y6, Canada.
  • 8 Department of Chemistry, Faculty of Arts and Sciences, Université de Montréal, Montreal, QC H3T 1J4, Canada.
  • # Contributed equally.
PMID: 41123996 DOI: 10.1073/pnas.2501825122
Abstract

Intracellular pH (pHi) influences diverse cellular processes, including cell proliferation, metabolism, and migration, and is linked to metabolic diseases and Cancer. Protonation alters protein charge and conformation, modulating different aspects of protein function. How pHi fluctuations are sensed by signaling proteins and translated into cellular responses remains incompletely understood. Here, we reveal that pHi plays a key role in regulating the stability of the mitogen-activated protein kinase Extracellular signal-regulated kinase 3 (ERK3). Intracellular acidification markedly increases the half-life of ERK3, whereas alkalinization accelerates its degradation. The pH-dependent regulation of ERK3 is rapid, reversible, and consistent across cell types. Mechanistically, we identified a region in the C-terminus of ERK3 that contains pH-sensing motifs. We further show by quantitative proteomics that short-term acidification or alkalinization globally affects the cellular proteome. Our findings underscore the critical role of pHi in ERK3 turnover and suggest a broader role for pH in regulating protein stability and cell signaling.

Keywords

ERK3; MAP kinases; intracellular pH; proteomics.

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