DEAD-Box Helicases: Sensors, Regulators, and Effectors for Antiviral Defense

Abstract

DEAD-box helicases are a large family of conserved RNA-binding proteins that belong to the broader group of cellular DExD/H helicases. Members of the DEAD-box helicase family have roles throughout cellular RNA metabolism from biogenesis to decay. Moreover, there is emerging evidence that cellular RNA helicases, including DEAD-box helicases, play roles in the recognition of foreign nucleic acids and the modulation of viral infection. As intracellular parasites, viruses must evade detection by innate immune sensing mechanisms and degradation by cellular machinery while also manipulating host cell processes to facilitate replication. The ability of DEAD-box helicases to recognize RNA in a sequence-independent manner, as well as the breadth of cellular functions carried out by members of this family, lead them to influence innate recognition and viral infections in multiple ways. Indeed, DEAD-box helicases have been shown to contribute to intracellular immune sensing, act as antiviral effectors, and even to be coopted by viruses to promote their replication. However, our understanding of the mechanisms underlying these interactions, as well as the cellular roles of DEAD-box helicases themselves, is limited in many cases. We will discuss the diverse roles that members of the DEAD-box helicase family play during viral infections.Viruses 2020, 12, 181 2 of 15 helicases to particular RNAs or proteins; the diversity of these regions accounts for the breadth of function observed within this protein family [7]. As a result of their diversity of binding and function, DEAD-box RNA helicases are involved in all aspects of cellular RNA metabolism, including transcription, splicing, microRNA biogenesis, ribosomal RNA processing, RNA export, translation, RNP granule formation, and decay [10]. Moreover, they are also involved in cellular stress responses, contributing to double-strand break (DSB) repair [11], stress granule formation, and antimicrobial responses [12]. DEAD-Box Helicases in Canonical Innate Immune SensingInnate immune defenses depend upon the recognition of invading pathogens by the host, and viral infections, including RNA viruses, are largely sensed through nucleic acid recognition. RNA viruses present a host cell with various foreign RNA features, such as unique ends, structured RNA elements, or dsRNA replication intermediates, which can be recognized as hallmarks of infection. RNA binding proteins thus play important roles in the sensing of viral infection, and DExD/H helicases are well-suited to recognize structural features characteristic of viral RNAs.The canonical cytoplasmic sensors of viral RNA, the RIG-I-like receptors (RLRs) RIG-I and MDA-5, contain DExD/H-box helicase domains [13]. RIG-I recognizes uncapped viral RNAsand short dsRNAs containing a 5 triphosphate, while MDA-5 binds longer dsRNA replication intermediates [13][14][15]. In addition to the helicase core domain, these proteins contain caspase activation and recruitment domains (CARDs).RNA recognition by these RLRs leads to oligomerization of ...

Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection

“…First we focused on the heterogeneous nuclear ribonucleoproteins (hnRNPs), a large set of adaptor proteins, and dead-box helicases, which remodel RNA structural elements (Geuens et al, 2016;Jankowsky, 2011) . These RBP families have a wide array of cellular functions and are often recovered with host or pathogenic RNAs in binding studies (Geuens et al, 2016;Meier-Stephenson et al, 2018;Taschuk and Cherry, 2020) . The hnRNP class showed robust interaction with all 4 viruses and similar enrichments for the majority of the 20 proteins we identified ( Figure 4A ).…”

Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell

“…Interestingly, other DExD/H-box helicases, such as DDX17, DDX21, DDX6 or DDX56, are also emerging as important sentinels that influence viral sensing in multiple ways. These helicases have been shown to bind vRNAs, acting either as antiviral effectors or contributing to viral replication [ 41 ].…”

Host protein chaperones, RNA helicases and the ubiquitin network highlight the arms race for resources between tombusviruses and their hosts

“…Whereas RNA helicases use ATP to modulate RNA structures/ functions, RNA chaperones perform those functions through binding to RNA targets without using ATP (Gilman et al, 2017;Linder and Jankowsky, 2011;Sharma and Jankowsky, 2014). Similar to cellular processes that depend on RNAs, (+)RNA viruses also require the involvement of RNA helicases and/or RNA chaperones to promote their replication and the infection process (Huang et al, 2010;Li and Nagy, 2011;Ranji and Boris-Lawrie, 2010;Taschuk and Cherry, 2020). The hosts also deploy cellular DEAD-box helicases, such as DICER, RIG-I or MDA5, which are involved in sensing the viral RNAs and initiating antiviral immune signaling or the RNAi pathway to destroy viruses (Ding, 2010;Garcia-Ruiz et al, 2010;Schroder, 2011;Taschuk and Cherry, 2020).…”