ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells

Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes (<i>TSC1</i> or <i>TSC2</i>) and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Here, we report that E26 transformation-specific (ETS) variant transcription factor 2 (ETV2) is a critical regulator of <i>Tsc2</i>-deficient cell survival. ETV2 nuclear localization in <i>Tsc2</i>-deficient cells is mTORC1-independent and is enhanced by spleen tyrosine kinase (Syk) inhibition. In the nucleus, ETV2 transcriptionally regulates poly(ADP-ribose) polymerase 1 binding protein (PARPBP) mRNA and protein expression, partially reversing the observed down-regulation of PARPBP expression induced by mTORC1 blockade during treatment with both Syk and mTORC1 inhibitors. In addition, silencing Etv2 or <i>Parpbp</i> in <i>Tsc2</i>-deficient cells induced ER stress and increased cell death in vitro and in vivo. We also found <i>ETV2</i> expression in human cells with loss of heterozygosity for <i>TSC2</i>, lending support to the translational relevance of our findings. In conclusion, we report a novel ETV2 signaling axis unique to Syk inhibition that promotes a cytocidal response in <i>Tsc2</i>-deficient cells and therefore maybe a potential alternative therapeutic target in LAM.