Intracellular pH regulates β-catenin with low pHi increasing adhesion and signaling functions

Abstract

Intracellular pH (pHi) dynamics are linked to cell processes including proliferation, migration, and differentiation. The adherens junction (AJ) and signaling protein β-catenin has decreased abundance at high pHi due to increased proteasomal-mediated degradation. However, the effects of low pHi on β-catenin abundance and functions have not been characterized. Here, we show that low pHi stabilizes β-catenin in epithelial cells using population-level and single-cell assays. β-catenin abundance is increased at low pHi and decreased at high pHi. We also assay single-cell protein degradation rates to show that β-catenin half-life is longer at low compared to high pHi. Importantly, we show that AJs are not disrupted by β-catenin loss at high pHi due to rescue by plakoglobin. Finally, we show that low pHi increases β-catenin transcriptional activity in single cells and is indistinguishable from a Wnt-on state. This work characterizes pHi as a rheostat regulating β-catenin abundance, stability, and funcion and implicates β-catenin as a molecular mediator of pHi-dependent cell processes.SummaryIntracellular pH (pHi) regulates the degradation rate of the pH sensor β-catenin, altering protein abundance, localization, and function in epithelial cells. This work shows pHi acts as a rheostat to alter both adhesion and signaling functions of β-catenin.