Sensing plasma membrane pore formation induces chemokine production in survivors of regulated necrosis

Although overwhelming plasma membrane integrity loss leads to cell lysis and necrosis, cells can tolerate a limited level of plasma membrane damage, undergo ESCRT-III-mediated repair, and survive. Here, we find that cells which undergo limited plasma membrane damage from the pore-forming actions of MLKL, GSDMD, perforin, or detergents experience local activation of PKCs through Ca2+ influx at the damage sites. S660-phosphorylated PKCs subsequently activate the TAK1/IKKs axis and RelA/Cux1 complex to trigger chemokine expressions. We observe that in late-stage cancers, cells with active MLKL show expression of CXCL8. Similar expression induction is also found in ischemia-injured kidneys. Chemokines generated in this manner are also indispensable for recruiting immune cells to the dead and dying cells. This plasma membrane integrity-sensing pathway is similar to the well-established yeast cell wall integrity signaling pathway at molecular level, and this suggests an evolutionary conserved mechanism to respond to the cellular barrier damage. [Display omitted] •Sub-lethal plasma membrane pore-forming damage induces chemokine production•S660 p-PKCs sense the pore-forming damage by detecting the local Ca2+ influx•Plasma-membrane-damage-induced chemokine production occurs in pathological conditions•This pathway works in parallel to the yeast cell wall integrity pathway Cells can tolerate sub-lethal plasma membrane pore-forming damage by activating repair mechanisms. Wang et al. show that S660 p-PKCs can sense pore-forming damage by detecting local Ca2+ influx, resulting in chemokine production. This pathway works in parallel with the yeast cell wall integrity pathway and occurs in multiple pathological conditions.