Rac1/ROCK-driven membrane dynamics promote Natural Killer cell cytotoxicity via necroptosis

Abstract

Natural Killer (NK) cells play a key role in eliminating virus-infected cells and cancer cells.Although molecular machineries mediating their activity and specificity have been extensively studied, our understanding of the determinants that govern the differential cytotoxicity of NK cells against distinct epithelial cell targets is still limited. By employing a live-cell FRET reporter and quantitative single cell imaging, we characterized the dynamic phenotypes and rate-limiting kinetics of a panel of normal and epithelial cancer cells to killing by primary human NK cells. We uncovered intriguing target-dependent variability in their sensitivity to three distinct NK cell cytotoxic modes mediated by granzyme, death ligand and the largely unexplored necrosis. While NK-target cell interaction via known inhibitory and activating receptors, in particular the KIRs, largely determined the overall cytotoxic activity, we found the variable sensitivity to distinct NK cell cytotoxic modes was not regulated by individual receptors. Instead, plasma membrane dynamics driven by blebs and/or lamellipodia appeared to control the induction of different cytotoxic modes in a target-specific manner, particularly promoting necrotic killing. Our results point to modulating the membrane dynamics of epithelial cell targets as a viable strategy to control the degree, timing and inflammatory consequences of NK cell killing.

Curcumin Inhibits Lysophosphatidic Acid Mediated MCP-1 Expression via Blocking ROCK Signalling

“…In another human aortic SMC, LPA stimulated MCP-1 is Rac-1 dependent as the transfection of negative Rac-1 mutant inhibited this response [ 16 ]. Rho is an upstream of ROCK, while Rac-1 regulates the downstream of ROCK and cytoskeleton rearrangement [ 45 , 46 ]. Therefore, these data together with our observation support that LPA mediated MCP-1 expression is ROCK signalling dependent.…”