Endomembrane targeting of human OAS1 p46 augments antiviral activity

Abstract

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies

“… 76 , 128 , 129 The protective effects of protein OAS1 in COVID-19 risk may be due to increased levels of p46 isoform, 73 , 78 which was later verified in a human genetic analysis. 130 ACE2 is a functional receptor for SARS-CoV-1 and SARS-CoV-2. 131 , 132 Human recombinant soluble ACE2 (hrsACE2) reduced SARS-CoV-2 viral load in infected Vero-E6 cells 133 and its role as a therapeutic target for COVID-19 is currently being explored in a phase II clinical trial (NCT04335136).…”

S-farnesylation is essential for antiviral activity of the long ZAP isoform against RNA viruses with diverse replication strategies

“…First, it could localize to cytoplasmic membranes to target viruses that enter the cell through endocytosis or replicate in specific compartments derived from these membranes. This hypothesis has been proposed to explain why the OAS1 p46 isoform, which has a CaaX box and is prenylated, is more antiviral against several positive strand RNA viruses than the p42 isoform that does not contain a CaaX box [ 68 , 69 ]. This hypothesis is also consistent with previous studies demonstrating that ZAP-L is more active than ZAP-S against Sindbis virus [ 15 , 48 , 49 ].…”

Inducible CRISPR activation screen for interferon-stimulated genes identifies OAS1 as a SARS-CoV-2 restriction factor

“…In agreement with Wickenhagen et al . and Soveg et al ., [ 31 , 32 ] we also identified OAS1 (2′-5′-oligoadenylate synthetase 1) as a SARS-CoV-2 restriction factor capable of inhibiting viral infection and the generation of progeny virus. Taken together, our findings demonstrate the utility of a novel inducible CRISPRa platform for antiviral genetic screens and identify multiple ISGs capable of restricting SARS-CoV-2.…”

“…TRIM25, an interferon-induced E3 ubiquitin ligase that enhances antiviral responses downstream of RIG-I, has been shown to interact specifically with SARS-CoV-2 RNA and thereby reduce infection [ 30 ]. During preparation of this manuscript, two additional studies employing different expression systems and screening methodologies highlighted the prominent role of OAS1 in restricting SARS-CoV-2 [ 31 , 32 ].…”