The cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited

Tumor necrosis factor (TNF) has a critical role in diverse cellular events including inflammation, apoptosis and necroptosis through different signaling complexes. However, little is known about how the transition from inflammatory signaling to the engagement of death pathways is modulated. Here we report that the cytoplasmic retinoic acid receptor gamma (RAR gamma) controls receptor-interacting protein kinase 1 (RIP1)-initiated cell death when cellular inhibitor of apoptosis (cIAP) activity is blocked. Through screening a short hairpin RNA library, we found that RAR gamma was essential for TNF-induced RIP1-initiated apoptosis and necroptosis. Our data suggests that RAR gamma initiates the formation of death signaling complexes by mediating RIP1 dissociation from TNF receptor 1. We demonstrate that RAR gamma is released from the nucleus to orchestrate the formation of the cytosolic death complexes. In addition, we demonstrate that RAR gamma has a similar role in TNF-induced necroptosis in vivo. Thus, our study suggests that nuclear receptor RAR gamma provides a key checkpoint for the transition from life to death.