Acidosis Regulates Microtubule Dynamics via the β1 Integrin/RhoA/CRMP-2 Axis

Microtubules are dynamic cytoskeletal filaments that have important organizing roles in all eukaryotic cells. Early in vitro studies on the effect of pH on microtubule stability focused on microtubules isolated from whole cell lysates, which can only replicate changes in intracellular pH. However, how extracellular pH can affect microtubule dynamics remains unclear. Here, we report that acidosis activates β1 integrin by increasing its affinity for RGD-containing ligands through the displacement of divalent ions in the metal-ion-binding sites of β1 integrin extracellular domain via protonation of Asp138. This induces the activation of RhoA and its downstream effector ROCK, which, via phosphorylation of Collapsin Response Mediator Protein-2 (CRMP-2), negatively regulates microtubules stability and changes the positioning and architecture of the Golgi apparatus. Thereby, extracellular pH modulates microtubule dynamics, which could have important consequences for intracellular organization, cell polarization, vesicular trafficking, nucleocytoplasmic shuttling, and cell division. There are multiple processes in human physiology associated with acidosis. The presented mechanochemical mechanism that links low extracellular pH and microtubule stability may serve as a blueprint for advancing our knowledge of cellular transport and exploring potential targets for drug development.