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Untangling the roles of RNA helicases in antiviral innate immunity

['Morgane Baldaccini', 'Université De Strasbourg', 'Architecture Et Réactivité De L Arn', 'Institut De Biologie Moléculaire Et Cellulaire Du Cnrs', 'Strasbourg', 'Sébastien Pfeffer']

Date: 2022-01 

One of the first layers of protection that metazoans put in place to defend themselves against viruses rely on the use of proteins containing DExD/H-box helicase domains. These members of the duplex RNA–activated ATPase (DRA) family act as sensors of double-stranded RNA (dsRNA) molecules, a universal marker of viral infections. DRAs can be classified into 2 subgroups based on their mode of action: They can either act directly on the dsRNA, or they can trigger a signaling cascade. In the first group, the type III ribonuclease Dicer plays a key role to activate the antiviral RNA interference (RNAi) pathway by cleaving the viral dsRNA into small interfering RNAs (siRNAs). This represents the main innate antiviral immune mechanism in arthropods and nematodes. Even though Dicer is present and functional in mammals, the second group of DRAs, containing the RIG-I-like RNA helicases, appears to have functionally replaced RNAi and activate type I interferon (IFN) response upon dsRNA sensing. However, recent findings tend to blur the frontier between these 2 mechanisms, thereby highlighting the crucial and diverse roles played by RNA helicases in antiviral innate immunity. Here, we will review our current knowledge of the importance of these key proteins in viral infection, with a special focus on the interplay between the 2 main types of response that are activated by dsRNA.

Funding: Our work is funded by European Research Council (ERC-CoG-647455 RegulRNA, to SP) and Agence Nationale de la Recherche through the Interdisciplinary Thematic Institute IMCBio, part of the ITI 2021-2028 program of the University of Strasbourg, CNRS and Inserm (ANR-10-IDEX-0002 and ANR-17-EURE-0023, to SP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction

To ward off viral infections, cells rely on a large variety of mechanisms that have been refined throughout evolution. During the initial response to an infection, the defense put in place will mainly consist in detecting the invading pathogen via the sensing of specific molecular patterns, which, in turn, will either trigger a signaling cascade or act directly on the detected molecule to hamper its function and/or degrade it. Different danger signals exist, but the presence of a foreign nucleic acid in the cell is one of the most prominent. Thus, the accumulation of DNA in the cytoplasm of eukaryotic cells, or of aberrant RNA molecules that do not possess the hallmarks of cellular RNAs, will immediately result in the onset of an innate immune response. Among the molecular features that are commonly associated with these pathogenic RNAs we can cite the presence of a 5′ triphosphate instead of a 5′ cap or of a double-stranded structure. In fact, double-stranded RNA (dsRNA) accumulates in cells infected by almost all viruses. While for RNA viruses, dsRNA is either generated during replication or by base pairing of single-stranded RNA regions within the genome, it can originate from convergent transcription for DNA viruses [1]. Therefore, dsRNA is a potent pathogen-associated molecular pattern (PAMP), which is recognized by both cytosolic and membranous receptors named pattern recognition receptors (PRRs). Upon dsRNA sensing, PRRs act in 2 different ways: either directly as effector molecules or indirectly as signal transducers. These receptors can be grouped into 3 different families: the Toll-like receptors (TLRs), the cytosolic NOD-like receptors (NLRs), and the cytosolic RIG-I-like receptors (RLRs) [2], which will be the subject of this review.

RLRs belong to a class of helicase-containing proteins able to sense nucleic acid to induce an antiviral response. They use ATP to bind to and/or unwind nucleic acids, thereby altering ribonucleoprotein complexes. Structural and sequence features that have been observed in archaea, bacteria, and eukaryotic cells allowed to classify RNA helicases into different superfamilies (SFs) [3]. Only SF1 and SF2 include helicases containing 2 bacterial RecA-like fold domains. The DExD/H-box helicase proteins family we are interested in are found within the SF2 subgroup [3]. This family is composed of RNA helicases involved in all aspects of RNA metabolism but also in antiviral defense [4,5]. These proteins can either unwind RNA upon ATP binding and hydrolysis or clamp around RNA to act as a platform to recruit other proteins [6].

Within the DExD/H-box helicases family, the subgroup of duplex RNA–activated ATPases (DRAs) is composed of SF2 helicases activated by dsRNA [7]. DRAs share the same activation mechanism: upon dsRNA binding, they undergo conformational changes to become catalytically active [8]. However, due to significant differences in their protein domain organization and their functions [6,8], we can distinguish signaling DRAs (sDRAs) and catalytic DRAs (cDRAs). These proteins include RLRs and Dicer proteins, which share a similar helicase domain [7,8] and participate in 2 main antiviral pathways, namely the RNA interference (RNAi) and the type I interferon (IFN) response. Here, we will focus on metazoan DRAs and more specifically on the 3 mammalian RLRs (RIG-I, MDA5, and LGP2), the mammalian Dicer, the 2 Drosophila melanogaster Dicers (dmDicer-1 and dmDicer-2), the Caenorhabditis elegans Dicer (ceDicer), and the 3 C. elegans Dicer-related helicases (DRH-1 to 3) [7]. We will discuss the role of DRAs as direct effectors of the antiviral response, before reviewing their roles as signaling molecules. Finally, we will elaborate on the noncanonical roles played by DRAs during viral infection in the light of recently published data and will comment on the possible crosstalk that can exist between pathways.

[END]

[1] Url: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010072

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