| DDX3 (DDX3X) is a highly conserved DEAD‑box RNA helicase that shuttles between nucleus and cytoplasm and acts as an ATP‑dependent RNA remodeler in multiple RNA processing and signaling contexts, including translation control, stress responses, and innate antiviral defense. The helicase core contains the canonical Walker A/B motifs and conserved DEAD sequence that couple ATP binding and hydrolysis to RNA unwinding and RNP remodeling, flanked by N‑ and C‑terminal low‑complexity regions that mediate interactions with translation factors, signaling adaptors, and components of stress granules, allowing DDX3 to integrate into distinct ribonucleoprotein complexes. In the cytoplasm, DDX3 associates with the 5′ UTRs of structured mRNAs and with factors such as eIF4E and eIF4G to promote translation initiation of transcripts with complex secondary structures, including mRNAs encoding regulators of proliferation and antiviral signaling like Rac1, TAK1, PACT, and STAT1; DDX3 knockdown reduces their translation and dampens both oncogenic and antiviral responses. As an innate immune sensor, DDX3 binds viral RNAs and functions as an atypical pattern-recognition receptor that cooperates with RIG‑I–like receptors: it interacts with the mitochondrial adaptor MAVS, TBK1, and IKKε at the outer mitochondrial membrane, and this complex formation enhances IRF3 and NF‑κB activation and type I interferon gene induction in response to RNA virus infection. DDX3 is also required for efficient RIG‑I pathway activation by supporting translation of PACT and facilitating K63‑linked ubiquitination and activation of RIG‑I, thereby positioning it upstream and downstream of key antiviral nodes in the MAVS–TBK1–IRF3 cascade. Viral pathogens exploit these functions: DDX3 is co‑opted by HIV‑1 and HCV as a cofactor for viral RNA export and translation, while HIV‑1 can simultaneously interfere with MAVS‑dependent signaling after DDX3‑mediated sensing of abortive transcripts, illustrating the double‑edged nature of this helicase in infection biology. In cancer, DDX3 displays context‑dependent tumor‑suppressive and oncogenic roles. In hepatocellular carcinoma, DDX3 expression is frequently reduced relative to normal liver, and restoring DDX3 decreases cell viability, migration, and stem‑like properties while inducing tumor‑suppressive microRNAs and transcriptional activation of p21, supporting a role as a growth suppressor whose loss promotes HCC progression and therapy resistance. In contrast, in breast and lung cancers and some other tumor types, DDX3 is overexpressed and required for efficient translation of oncogenic mRNAs and for hypoxia‑induced adaptation via HIF‑1α‑driven upregulation, and high DDX3 correlates with aggressive clinical behavior. |
