OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Cytoplasmic double-stranded RNA (dsRNA) is recognized by RIG-I-like receptors (RLRs).
• RLR activation induces type I interferons (IFN-Is), pro-inflammatory cytokines, and apoptosis.
• Tumor cells are a key target for immune-mediated destruction.

Purpose of the Study:

• To elucidate the signaling mechanisms by which 5'-triphosphate RNA (3p-RNA), a RIG-I ligand, induces cytokine secretion and apoptosis in tumor cells.
• To differentiate the roles of RLRs and other dsRNA sensors in these cellular responses.

Main Methods:

• Affinity purification coupled with mass spectrometry to identify 3p-RNA binding proteins.
• Functional assays using RNase L-deficient cells to assess apoptosis induction.
• Analysis of apoptotic pathways, including NOXA and MCL-1 expression.

Main Results:

• RIG-I-like receptors (RLRs) are essential for cytokine production and IFN-I-mediated priming but not for 3p-RNA-induced apoptosis.
• 3p-RNA directly binds and activates oligoadenylate synthetase 1 (OAS1) and RNase L.
• RNase L deficiency significantly impairs 3p-RNA-induced apoptosis, which requires translational arrest and NOXA upregulation to deplete MCL-1.

Conclusions:

• 3p-RNA-induced apoptosis in tumor cells is a two-step process.
• The first step involves RIG-I-dependent priming of effector pathways.
• The second step is an RNase L-dependent effector phase leading to intrinsic apoptosis.