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

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.