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The cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited
Qing Xu1, Siriporn Jitkaew1,2, Swati Choksi1
1Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, MD, 20892, USA.
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.
Insights
Retinoic acid receptor gamma (RARγ) controls cell death pathways initiated by tumor necrosis factor (TNF) when apoptosis inhibitors are blocked. RARγ moves from the nucleus to cytoplasm, promoting RIP1-initiated cell death signaling complexes.
Area of Science:
- Cellular Biology
- Molecular Signaling
- Immunology
Background:
- Tumor necrosis factor (TNF) mediates critical cellular events like inflammation and programmed cell death (apoptosis and necroptosis).
- The precise molecular mechanisms governing the switch between TNF-induced inflammation and cell death signaling remain incompletely understood.
- Understanding this transition is crucial for developing targeted therapies for diseases involving aberrant cell death signaling.
Purpose of the Study:
- To elucidate the role of cytoplasmic retinoic acid receptor gamma (RARγ) in modulating TNF-induced cell death pathways.
- To identify the molecular players and mechanisms involved in the transition from inflammatory to death signaling complexes.
- To investigate the potential therapeutic implications of targeting RARγ in TNF-mediated cell death.
Main Methods:
- Screening of a short hairpin RNA library to identify factors essential for TNF-induced cell death.
- Biochemical assays to analyze the formation of TNF-receptor signaling complexes.
- Cellular fractionation to track the subcellular localization of RARγ.
- In vivo studies to assess the role of RARγ in TNF-induced necroptosis.
Main Results:
- Retinoic acid receptor gamma (RARγ) was identified as essential for TNF-induced receptor-interacting protein kinase 1 (RIP1)-initiated apoptosis and necroptosis, particularly when cellular inhibitor of apoptosis (cIAP) activity is blocked.
- RARγ orchestrates the formation of death signaling complexes by mediating the dissociation of RIP1 from TNF receptor 1 (TNFR1).
- RARγ translocates from the nucleus to the cytoplasm to facilitate the assembly of these death complexes, and this function is conserved in vivo during TNF-induced necroptosis.
Conclusions:
- Nuclear receptor RARγ acts as a critical checkpoint, controlling the switch between pro-survival and pro-death signaling downstream of TNF.
- RARγ's cytoplasmic function is key to initiating RIP1-dependent cell death pathways, offering a novel target for therapeutic intervention.
- This study reveals a previously unappreciated role for RARγ in regulating programmed cell death, with significant implications for understanding inflammation and cancer biology.
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