DEAD-box helicase 3 (DDX3) is a protein with diverse cellular roles. It belongs to the DEAD-box protein family, characterized by an Asp-Glu-Ala-Asp (DEAD) motif. These proteins function as ATP-dependent RNA helicases, unwinding RNA structures using energy from ATP. In humans, DDX3 exists as two forms: DDX3X, found on the X chromosome and expressed throughout the body, and DDX3Y, located on the Y chromosome and predominantly found in male germline cells. Both forms are closely related and perform similar functions, including protein synthesis.
The Core Functions of DDX3
DDX3 is involved in various aspects of RNA metabolism, the process by which genetic information is used to create proteins. It participates in messenger RNA (mRNA) splicing, removing non-coding regions from RNA. DDX3 also plays a role in transporting mRNA from the nucleus to the cytoplasm, ensuring it reaches the protein-making machinery. It is also implicated in the initiation of translation, where mRNA instructions are read to build proteins.
The protein also helps regulate gene expression, influencing gene activation or repression. DDX3 interacts with transcription factors and gene promoters, activating or repressing specific RNA molecule production. This regulatory capacity extends to controlling the cell cycle, the events leading to cell division. DDX3 influences cell cycle phase transitions by impacting the translation of regulators like cyclin E1.
DDX3 also plays a part in the innate immune response, the body’s first line of defense against infections. It helps cells recognize viral invaders and activate antiviral defenses. DDX3 contributes to the production of type I interferons, signaling molecules that alert neighboring cells to a viral threat and trigger antiviral states. It can also enhance the activation of interferon regulatory factor 3 (IRF3), which promotes interferon production.
DDX3 and Disease
DDX3’s involvement in fundamental cellular processes means its dysregulation can contribute to various human diseases. Its role in cancer is complex, acting as both a promoter of growth (oncogene) and a suppressor of tumors, depending on the cancer type. For example, DDX3X has been linked to breast cancer, melanoma, and colon cancer, sometimes promoting tumor progression by activating pathways like MAPK or regulating cell cycle repressors. Conversely, in certain colorectal cancers, loss of DDX3 can advance the disease.
In neurological disorders, mutations in the DDX3X gene are associated with DDX3X syndrome. This neurodevelopmental disorder leads to intellectual disability and other developmental challenges. Symptom severity often correlates with the degree to which the DDX3X protein’s normal activity is reduced.
DDX3 also interacts with numerous viruses, influencing their ability to replicate within host cells. Viruses like HIV, Hepatitis C virus (HCV), and SARS-CoV-2 often manipulate DDX3 to facilitate their life cycles. For instance, the HCV core protein can interact with DDX3, potentially hindering the host’s antiviral immune response by affecting DDX3’s role in detecting viral RNA. DDX3 can also play a direct role in the host’s antiviral response, contributing to the detection of viral nucleic acids and the activation of immune pathways.
Research and Therapeutic Implications
Given DDX3’s widespread involvement in normal cellular functions and disease processes, it is a subject of significant research for its potential as a therapeutic target. Scientists are exploring ways to modulate DDX3 activity, particularly for cancer and viral infections. Inhibitors designed to block DDX3’s function are being developed to disrupt disease progression. These inhibitors have shown promise in suppressing viral replication in cell cultures and exhibiting anticancer activity against several cancer types, often without significant toxicity.
Beyond inhibition, researchers are investigating other strategies to exploit DDX3 for medical benefit. This includes exploring its potential as a diagnostic biomarker, a measurable indicator of a specific disease state. Continued research aims to unravel the intricate mechanisms by which DDX3 contributes to various diseases, paving the way for more targeted and effective treatments.