DExD/H-box RNA helicases as mediators of anti-viral innate immunity and essential host factors for viral replication

Abstract

a b s t r a c t a r t i c l e i n f oTraditional functions of DExD/H-box helicases are concerned with RNA metabolism; they have been shown to play a part in nearly every cellular process that involves RNA. On the other hand, it is accepted that DexD/H-box helicases also engage in activities that do not require helicase activity. A number of DExD/ H-box helicases have been shown to be involved in anti-viral immunity. The RIG-like helicases, RIG-I, mda5 and lgp2, act as important cytosolic pattern recognition receptors for viral RNA. Detection of viral nucleic acids by the RIG-like helicases or other anti-viral pattern recognition receptors leads to the induction of type I interferons and pro-inflammatory cytokines. More recently, additional DExD/H-box helicases have also been implicated to act as cytosolic sensors of viral nucleic acids, including DDX3, DDX41, DHX9, DDX60, DDX1 and DHX36. However, there is evidence that at least some of these helicases might have more downstream functions in pattern recognition receptor signalling pathways, as signalling adaptors or transcriptional regulators. In an interesting twist, a lot of DExD/H-box helicases have also been identified as essential host factors for the replication of different viruses, suggesting that viruses 'hijack' their RNA helicase activities for their benefit. Interestingly, DDX3, DDX1 and DHX9 are among the helicases that are required for the replication of a diverse range of viruses. This might suggest that these helicases are highly contested targets in the ongoing 'arms race' between viruses and the host immune system. This article is part of a Special Issue entitled: The Biology of RNA helicases -Modulation for life.

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

“…The fraction of DHX36 and G3BP foci containing G4DNA was significantly lower than the other stress granule proteins. Although DHX36 is known to associate with stress granules (33), it also has other roles in the cytoplasm such as sensing double-stranded RNA (42). The cytoplasmic localization of G3BP, combined with the inherent punctate staining observed with this antibody, likely results in reduced co-localization of G4DNA with G3BP foci.…”

DDX19A Senses Viral RNA and Mediates NLRP3-Dependent Inflammasome Activation

“…These results demonstrate that DDX19A specifically functions in HP-PRRSV RNA-induced IL-1b secretion by acting as the direct sensor, and other stimulators (such as polyI:C or ATP/LPS), respectively, activate NLRP3 inflammasome through different pathways. Recently, the DEAD/H-box helicase family members have been drawing more and more attention not only for their powerful capacities in detecting invading PAMPs as direct sensors (6, 36), but also for their key roles involved in viral replication (36,38,39,71). It has been demonstrated that DDX3 binds the HCV core FIGURE 8.…”

“…DEAD/H-box RNA helicases are involved in various RNA metabolic processes, including transcription, RNA transport, and RNA degradation (35,36). Several studies showed that some DEAD/H-box RNA helicases are involved in NLRP3 inflammasome activation and viral replication (6,(37)(38)(39)(40).…”

Innate recognition of microbial-derived signals in immunity and inflammation

“…In contrast, MDA5 recognizes long poly(I:C) and long dsRNA (1-2 kb), which is produced during replication of sense-strand ssRNA viruses. Additional DExD/H-box helicases including DDX3, DHX9, DDX60 and DHX36 have also been recently reported to act as cytosolic sensors of viral nucleic acids (Fullam and Schröder, 2013). Moreover, interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of proteins in the preferential binding to mis-or un-modified RNA and the viral replication proteins in the cytoplasm (Vladimer et al, 2014).…”