viruses Article ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections Barkha Ramnani, Praveen Manivannan, Sarah Jaggernauth and Krishnamurthy Malathi *   Citation: Ramnani, B.; Manivannan, P.; Jaggernauth, S.; Malathi, K. ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections. Viruses 2021, 13, 315. https://doi.org/ 10.3390/v13020315 Academic Editor: Craig McCormick Received: 22 January 2021 Accepted: 16 February 2021 Published: 18 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USA; Barkha.Ramnani@rockets.utoledo.edu (B.R.); Praveen.Manivannan@rockets.utoledo.edu (P.M.); Sarah.Jaggernauth@rockets.utoledo.edu (S.J.) * Correspondence: Malathi.Krishnamurthy@utoledo.edu Abstract: 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. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, 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 and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a 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. Keywords: RNase L; ABCE1; RLI; autophagy; interferon; apoptosis 1. Introduction Degrading viral and cellular RNAs required for viral replication is an evolutionar- ily conserved antiviral mechanism. In higher vertebrates, this process is regulated by interferon (IFN), produced during a viral infection through the activation of the ubiqui- tous cellular latent endoribonuclease, ribonuclease L (RNase L). The 2 ′ ,5 ′ -oligoadenylate synthetase (OAS)/RNase L system is an innate immune pathway that responds to the double-stranded RNAs (dsRNAs) that serve as pathogen-associated molecular patterns (PAMPs) to induce the degradation of viral and cellular RNAs, thereby blocking the viral infection [1–3]. Type I IFN, produced and secreted by a virus-infected cell signal through the type I IFN receptor, activates JAK-STAT signaling and induces the expression of interferon-stimulated genes (ISGs), including oligoadenylate synthetases (OAS), that together establish the antiviral state [4,5]. OAS1–3 isoforms are expressed at varying levels in different cell types, and on activation by dsRNA PAMPs, certain OAS proteins produce 2-5A from cellular ATP [6–8]. 2-5A is a unique ligand that binds monomeric and latent RNase L with high affinity, causing RNase L dimerization and activation. Active RNase L cleaves diverse single-stranded RNA substrates, including viral genomes and cellular RNAs, directly impacting protein synthesis and limiting viral replication [3]. Activation of RNase L, through the generation of dsRNA cleavage products, amplifies IFN production, activates inflammasome, leads to autophagy, and promotes a switch from autophagy to apoptosis, affecting viral replication in cells [9–13]. Viruses 2021, 13, 315. https://doi.org/10.3390/v13020315 https://www.mdpi.com/journal/viruses