Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction

Cytosolic phospholipase A2 (cPLA₂) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca²⁺ and INM tension (T_INM) are thought to govern the interactions and activity of cPLA₂ 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 cPLA₂ 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 cPLA₂-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 Ca²⁺-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 cPLA₂ activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger.