Cellular Mg2+ decrease causes a distinctive NF-?B-dependent form of cell death

Mg2+ is an essential cofactor for numerous enzymes, supporting fundamental cellular processes. Phosphatase of regenerating liver (PRL) protein family, inhibits cyclin M (CNNM) Mg2+ efflux transporters. To elucidate the physiological role of PRL in Mg2+ homeostasis at the cellular level, we employed combined genetic knockout and knockdown approaches. Such PRL KO + KD led to marked reduction of intracellular Mg2+ levels and triggered extensive cell death. To investigate the mechanism underlying cell death induced by PRL KO + KD, we next performed transcriptomic analysis to profile the changes in global gene expression, which revealed activation of the NF-?B pathway, and accordingly, genetic deletion of NF-?B p65 subunit abrogated cell death. Similarly, CNNM overexpression triggered intracellular Mg2+ decrease, NF-?B activation and subsequent cell death. Notably, this form of cell death exhibited unique morphological features, including actin-driven fiber-like protrusions, distinguishing it from known cell death modalities. Our findings uncover a previously unrecognized mode of NF-?B-dependent cell death triggered by intracellular Mg2+ decrease. Overall design: RNA-seq analysis of wild-type or PRL2-/-; PRL1+/- cells transfected with control or PRL1-siRNA