Role of DEAD/DEAH-box helicases in immunity, infection and cancers

Abstract

DEAD/DEAH-box helicases (DDX) are integral RNA-binding proteins within the RNA helicase superfamily 2 (SF2), characterized by distinct DEAD (Asp-Glu-Ala-Asp) and DEAH (Asp-Glu-Ala-His) motifs. These motifs delineate two subfamilies: DEAD-box (DDX) and DEAH-box (DHX). DEAD-box proteins predominantly facilitate localized non-processive RNA duplex destabilization, whereas DEAH-box helicases mediate processive RNA translocation and unwinding. This functional dichotomy is attributed to Asp-to-His substitution in the DEAH motif, which modulates ATP hydrolysis and conformational dynamics. DEAD-box helicases have been implicated in critical cellular processes, including translation, splicing, and RNA decay. In contrast, DEAH-box proteins play pivotal roles in splicing, ribosome biogenesis, and RNA export. DEAD/DEAH-box helicases play crucial roles in various cellular processes, and their regulation is primarily governed by post-translational modifications (PTMs) and protein-protein interactions (PPIs), particularly within their N- and C-terminal sequences. Despite extensive research, significant knowledge gaps persist regarding their regulation, cofactor roles, substrates, PPIs, mutation effects, and involvement in signaling cascades. Mutations in DEAD domains have been associated with dysregulated immune signaling and have been implicated in various cancers, underscoring their importance in disease pathogenesis. Specific helicases, including DDX3, DDX5, DDX6, and DDX41, have been extensively studied for their roles in immune response regulation, antiviral defense, and cellular stress response. This review critically examines the DEAD-box helicases involved in cell cycle regulation and their inhibitors, as well as those that regulate the Toll-like receptor signaling pathway. Furthermore, we provide comprehensive insights into the phosphorylation-based regulation of major DDX members, with a particular focus on DDX3X, DDX21, and DDX42 in various cancers. Elucidating the molecular mechanisms, regulatory influences, and therapeutic potential of DEAD/DEAH-box helicases is of paramount importance, particularly in the fields of infectious diseases and immune modulation. This review provides current knowledge and identifies critical areas for future research, aiming to advance our understanding of these essential molecular machines and their potential as therapeutic targets.

Keywords: DEAD-box helicases; Immune responses; Post-translational modifications; Protein–protein interactions; RNA helicases; TLR signaling pathway.

Fig. 1

Bar plot displaying the number of publications for each member of the DEAD box helicase family. The y axis represents the total number of publications in the last 10 years, while the x axis lists the individual DEAD box helicase members

Fig. 2

General structure of DEAD/DEAH box helicases. The figure illustrates the domains and motifs of DEAD box RNA helicase and DEAH box helicase, which form a helicase core containing conserved motifs necessary for ATP binding and hydrolysis (blue), RNA binding (gray), and both ATP and RNA linked communication motifs (yellow). The two RecA like domains, RecA like domains I and RecA like domains II, form the helicase core. Variable N terminal and C terminal regions are shown at both ends (blue). DEAH box helicase illustrates the domain architecture using the same color scheme as in DEAD box helicase, with conserved C terminal domains consisting of a winged helix, Ratchet like domain, and oligosaccharide binding fold domains

Fig. 3

DEAD box proteins involved in cell cycle regulation. This diagram provides a detailed overview of cell cycle regulation, focusing on the involvement of DEAD box (DDX) proteins at various checkpoints: G1, S, G2, and M phases. Specific DDX proteins are associated with different stages of the cell cycle and play critical roles in progression and regulation. The figure also delineates the action of various inhibitors on DDX proteins and their targeted effects on cell cycle arrest at distinct checkpoints. Additionally, the impact of these inhibitors on non DDX proteins involved in cell cycle control is depicted, demonstrating the broad potential of these compounds for cell cycle intervention

Fig. 4

Regulatory role of DEAD/H box helicases in the toll like receptor (TLR) signaling pathway. Figure illustrates the specific involvement of various DEAD/H box proteins, such as DDX1, DDX3, DDX21, DDX24, and others, in mediating the signal transduction process initiated by the recognition of pathogen associated molecular patterns (PAMPs), such as DNA and RNA, by endosomal TLRs (TLR7, TLR8, TLR9) and surface TLRs (TLR1, TLR3, TLR4, TLR6). Upon activation by these PAMPs, TLRs recruit helicases either directly or indirectly through adaptor proteins such as MyD88, TRIF, TRAF3, and TRAF6, leading to the downstream activation of transcription factors such as IRF3 and NFκB. This results in the translocation of these transcription factors into the nucleus, culminating in the expression of type I interferon (IFN α/β) genes and proinflammatory cytokines, which are critical for the innate immune response. The dotted lines in this figure indicate indirect interactions or pathways that have not been fully characterized

Fig. 5

Lollipop plot representing the frequency of phosphosites identified in experimental studies under various cancer conditions. The X axis represents the domain of DEAD Box helicase a. DDX3X, b. DDX21, and c.DDX42 . The Y axis represents the frequency of phosphosites in various cancer studies. Color coded stacked circles correspond to the different cancer types that reported the respective phosphosites