Helicases in Antiviral Immunity: Dual Properties as Sensors and Effectors

Abstract

Many helicases have a unique ability to couple cognate RNA binding to ATP hydrolysis, which can induce a large conformational change that affects its interaction with RNA, position along RNA, or oligomeric state. A growing number of these helicases contribute to the innate immune system, either as sensors that detect foreign nucleic acids and/or as effectors that directly participate in the clearance of such foreign species. We here discuss a few examples, including retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and Dicer, focusing on their dual functions as both sensors and effectors. We will also discuss the closely related, but less understood helicases, laboratory of genetics and physiology 2 (LGP2) and Dicer-related helicase-1 and -3 (DRH-1 and -3).

Standing on three legs: antiviral activities of RIG-I against influenza viruses

“…In line with this, it was reported that signalinginactive RIG-I can inhibit hepatitis B virus by binding to the 5 0 -e region of the pregenomic RNA [43 ], and that both RIG-I and MDA5 can actively displace viral proteins from dsRNA [44 ]. Thus, RIG-I has a previously unrecognized RIG-I vs. influenza virus Weber-Gerlach and Weber 73 direct antiviral effect that can precede antiviral signaling [3,45,46].…”

“…All three RLRs are RNA helicases, and RIG-I and MDA5 additionally possess N-terminal caspase recruitment domains (CARDs) to activate the antiviral signaling chain via the CARD-containing adapter MAVS [3]. Whereas RIG-I mainly responds to short 5 0 triphosphorylated (5 0 ppp) blunt-ended double-stranded (ds) RNA with a minimal length of 10 base pairs, MDA5 is triggered by longer double-stranded dsRNA, ideally with a higher-order structure [2,[4][5][6].…”

Discrimination of Self and Non-Self Ribonucleic Acids

“…Viral replication greatly enhances the abundance of stimulatory nucleic acids and thereby regulates the magnitude of the response (Rehwinkel and others 2010;Weber and others 2013). Both, viral RNA and DNA (vRNA/DNA) can stimulate pattern recognition receptors (PRRs) and recently molecular principles underlying the basis for detecting viruses and immune-stimulatory nucleic acids were discovered (Schlee 2013;Ahmad and Hur 2015). Besides activation of the innate immune system, viral nucleic acids modulate the activity of general cellular machineries such as protein translation, RNA degradation, or cell death ( Fig.…”

Dicer uses distinct modules for recognizing dsRNA termini

“…S1A). RLRs often function in innate immunity (8), and Dicer helicase domains sometimes show differences in activity that correlate with roles in immunity. For example, Drosophila melanogaster expresses two Dicers, one specialized for processing miRNAs (dmDcr-1), and a second for siRNAs (dmDcr-2) (9).…”

“…RIG-I distinguishes capped termini of cellular transcripts from tri- and di-phosphorylated termini of viral transcripts, and this is inferred to allow self versus non-self discrimination (8). We found that, like RIG-I, dmDcr-2 cannot efficiently process dsRNAs capped at the 5’-terminus, although the phosphorylation state does not affect cleavage (Fig.…”