How skin achieves mechano-resistance for land movement: the critical role of ER sensing

To adapt to gravitational forces during the transition to terrestrial life, animals evolved specialized paw skin to withstand their body weight and allow for locomotion. In a recent Cell article, Di et al. demonstrate SLURP1 as an endoplasmic reticulum (ER) membrane protein that protects palmoplantar keratinocytes from mechanical stress by preserving SERCA2b activity and inhibiting the pPERK-NRF2 signaling under mechanical pressure.