Abstract
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 (RARγ) 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 RARγ was essential for TNF-induced RIP1-initiated apoptosis and necroptosis. Our data suggests that RARγ initiates the formation of death signaling complexes by mediating RIP1 dissociation from TNF receptor 1. We demonstrate that RARγ is released from the nucleus to orchestrate the formation of the cytosolic death complexes. In addition, we demonstrate that RARγ has a similar role in TNF-induced necroptosis in vivo. Thus, our study suggests that nuclear receptor RARγ provides a key checkpoint for the transition from life to death.The molecular switch between how tumour necrosis factor (TNF) controls inflammation versus cell death is less well defined. Here, the authors show that the nuclear receptor retinoic acid receptor gamma is released from the nucleus to disrupt TNF initiated cell death complexes in the cytoplasm.