Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction

Cytosolic phospholipase A2 (cPLA ₂ ) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca ²⁺ and INM tension (T _INM ) are thought to govern the interactions and activity of cPLA ₂ at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent T _INM , the conditions permitting nuclear membrane mechanotransduction by cPLA ₂ or other mediators remain unclear. To test whether the ER buffers T _INM , we created the genetically encoded, Ca²⁺-insensitive T _INM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN– or cPLA ₂ –INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between T _INM and disrupted ER–nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca ²⁺ -induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers T _INM without preventing it. Besides consolidating the biomechanical basis of cPLA ₂ activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger.