DDX41 [DEAD (Asp-Glu-Ala-Asp) Box Polypeptide 41] is a cytosolic helicase sensor for dsDNA, DNA/RNA complexes, and cyclic dinucleotides (CDNs). Its N-terminal domain is responsible for translocation from the cytoplasm to the nucleus. Its DEAD domain, with its signature aspartate-glutamate-alanine-aspartate motif, is important for ATP-powered DNA/CDN detection and signaling. The remaining C-terminal domain functions as a helicase, unwinding the targeted nucleic acid structures.
Recent work has also found that DDX41 selectively regulates the alternative splicing of many genes involved in cell transformation and the immune response.1
DDX41 as Sensor
DDX41 was first characterized as a cytoplasmic dsDNA sensor, initiating an innate immune response to invading viruses and bacteria via the type 1 IFN system. While DDX41 is constitutively expressed in the cytosol of dendritic cells, macrophages, and neutrophils, it is typically bound to the E3 ubiquitin ligase, TRIM21, and, thereby, inactivated. In the presence of B DNA structures, DDX41 dissociates from TRIM21 and is phosphorylated by Bruton’s tyrosine kinase (BTK). BTK also aids DDX41’s interaction with STING (the stimulator of interferon genes). Via TBK1, downstream STING signaling activates transcription factors, such as IRF3 and NF-kappa beta, inducing the production of type 1 interferons and pro-inflammatory cytokines, such as TNF and IL-6. The tight control of DDX41 activation is essential to prevent the pathologies associated with excessive type 1 IFN expression, such as lupus erythematosus. Complement components, C3a and C5a, also act to limit the expression of DDX41.2
DDX41 as Suppressor
Mutations in the DEAD domain of DDX41 have been associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It is thought that DDX41 functions as a tumor suppressor through its functions in pre-mRNA splicing and RNA processing. In general, knockdowns or critical mutations in DDX41 have fostered tumor growth, while overexpression of intact DDX41 has inhibited it in various transformed cell lines. The cyclin-dependent kinase inhibitor, p21, has very different roles, depending upon its cellular localization. In the nucleus, it acts as a tumor suppressor. In the cytosol, it operates in an oncogenic manner. Intact DDX41 binds to p21 mRNA and inhibits its translation, suppressing its cytosolic proliferative activities. Frame-shifted mutations in the DEAD domain of DDX41 lose this ability to control p21 translation. Confusingly, loss of DDX41 function in colon cancer cells enables p21-mediated apoptosis. Perhaps, p53 status and/or tissue of origin play pivotal roles in determining how DDX41 influences tumorigenesis.3
DDX41 as Modulator
A recent study investigated the regulatory role of DDX41 in HeLa cells and cervical cancer. DDX41 typically acts as a tumor suppressor by inhibiting proliferation and promoting apoptosis in HeLa cells. However, upon DDX41 overexpression, the authors were able to distinguish and highlight the range of individual genes affected by this intervention. In short, overexpression of DDX41 down-regulated the expression of a host of oncogenes, up-regulated several tumor suppressors, regulated alternative splicing of genes in the FGF/FGFR progression axis, and up-regulated genes associated with the neoplastic immune response and antigen presentation. In particular, DDX41’s modulation of antigen presentation gene expression positively correlates with increased cervical cancer survival.4
DDX41’s effects on innate immunity and tumor progression open the window to new therapeutic interventions.
- Perculija, V. and Ouyang, S. (2018) Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases. Helicases from All Domains of Life, 141-171. https://www.sciencedirect.com/science/article/pii/B9780128146859000099
- Jiang, Y. et al. (2017) The Emerging Roles of DDX41 Protein in Immunity and Diseases. Protein and Cell, 8, 83-89. Review. https://doi.org/10.1007/s13238-016-0303-4
- Peters, D. et al. (2017) The DEAD-Box Helicase DDX41 is a Novel Repressor of p21WAF1/CIP1 mRNA Translation. Signal Transduction, 292(20), 8331-8341. https://doi.org/10.1074/jbc.M116.772327
- Qin, K. et al. (2021) DDX41 Regulates the Expression and Alternative Splicing of Genes Involved in Tumorigenesis and Immune Response. Oncology Reports, 45(3), 1213-1225. https://doi.org/10.3892/or.2021.7951