Degrading cellular and viral RNAs required for viral replication is an evolutionarily conserved antiviral mechanism. Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. RNase L activates different signaling pathways including: IFN production, inflammasome activation, inhibition of protein synthesis, autophagy, and apoptosis, to mount an antiviral response. My work has focused on the signaling role of RNase L-cleaved small RNAs and the impact of regulating RNase L activity on autophagy and apoptosis during viral infections.Host responses to viral infections, involve overlapping signaling pathways that regulate autophagy and apoptosis. How the crosstalk between these two evolutionarily conserved processes is integrated to determine the fate of a cell remains unclear and represents a critical gap in our understanding of host response to viral infections and itsivresolution. Ribonuclease L (RNase L) is a regulated endoribonuclease that is activated during viral infections and cleaves cellular including rRNAs in ribosomes and viral single-stranded RNAs, to generate small double-stranded RNAs. Double-stranded RNAs serve as pathogen associated molecular patterns (PAMPs) to stimulate interferon (IFN) production. The cytosolic Rig-like helicases (RLHs) and endosomal Toll- like receptors (TLRs), along with dsRNA-dependent protein kinase (PKR) and 2’-5’oligoadenylate synthetase (OAS) serve as dsRNA sensors in cells. Activation of RNase L induces autophagy via stress-activated c-jun N-terminal kinase (JNK) and PKR signaling pathways. Interestingly, RNase L, JNK and PKR are also components of pro-apoptotic pathways induced by dsRNA suggesting a role in crosstalk between autophagy and apoptosis. Previous studies show that RNase L-cleaved RNAs inhibit autophagy and promote apoptosis by cleaving a key autophagy protein, Beclin-1, however the receptors, signaling pathways and its impact on viral infections are not understood. My work shows that RIG-I and DHX15, but not PKR and OAS isoforms are required for RNase L-cleaved small RNAs induced apoptosis. Our studies demonstrate an overlapping role of RIG-I in dsRNA-induced apoptosis by interacting with DHX15, in addition to its canonical role in interferon induction, and that IPS-1 is required for apoptosis. Using biochemical and mutagenesis approaches along with gene knockout cells of RIG-I and/or DHX15, we show that RIG-I and DHX15 interact in response to RNase L activation, and RNA-binding activity of DHX15 is required for apoptosis induction. In cells depleted of RIG-I or DHX15, activation of transcription factors IRF-3 and NF-κB is significantly reduced with a corresponding decrease in IFN production and proinflammatory cytokines. However, apoptosis induction is independent of IFN-inducing abilities of IRF-3 and NF-κB as cells depleted of IRF-3 or compromisedvin NF-κB activity and cells defective in IFN signaling showed no rescue of cell death. IPS-1, a mitochondrial adaptor protein that coordinates RIG-I RNA signaling, is required for apoptosis by RNase L-cleaved RNAs as cells depleted of IPS-1 showed increased cell viability. RIG-I and DHX15 mediate RNase L-induced apoptosis by activating JNK and p38 MAP kinases as pharmacological inhibition of both kinases increased cell viability. Finally, RNase L exerts antiviral effect during Coxsackie virus B3 infection as cells lacking RNase L produce significantly higher titers of virus. Autophagy supports Coxsackie virus B3 replication, and the virus uses apoptosis for dissemination. Our results show that cells treated with RNase L cleaved RNAs induce premature apoptosis which significantly diminishes viral titers. In future, we would also like to determine the biochemical properties of RNase L-cleaved small RNAs on Coxsackie virus B3 (CVB3) pathogenesis by regulating autophagy and apoptosis. This study demonstrates the recruitment of unique dsRNA-binding proteins that activate specific, but overlapping signaling pathways, in coordinating RNA signals that impact IFN induction or cell death pathways to affect the outcome of viral infections.The OAS/RNase L pathway exerts antiviral effects against a wide range of viruses. Consequently, viruses have evolved mechanisms to counteract the antiviral activity of OAS/RNase L pathway by antagonizing or inhibiting activation of RNase L. Here, we show that ABCE1, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation andvisensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting an early switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects.