DDX6, also known as Rck/p54, is a highly conserved member of the DEAD-box family of helicases. It plays crucial roles in dynamic ribonucleoproteins, contributing to mRNA storage, translational repression, and decay. It is involved in pathways related to alternative translation initiation, miRNA-mediated silencing, and is essential for P-body function, which is associated with mRNA metabolism [4].

Suppression of DDX6 in human and mouse primed embryonic stem cells endows them with a differentiation-resistant state and allows for easy reprogramming to a naive state [1]. In adult progenitors, DDX6 controls the balance between self-renewal and differentiation [1]. In the context of stress granules and P-bodies, DDX6 limits stress granule formation and influences their composition and docking with P-bodies [2]. DDX6 also triggers the decay of inefficiently translated mRNAs in human cells [3]. In non-immune cells, DDX6-silencing suppresses the NF-κB pathway and inhibits activation of the IL-6 amplifier, while its forced expression enhances NF-κB promoter activity, suggesting its involvement in inflammatory disease pathogenesis [5]. In pancreatic cancer, DDX6 acts as an oncogene, promoting cell proliferation, cell cycle transition, and tumor formation, and it positively regulates the expression of KIFC1 [6].

In summary, DDX6 is a key regulator in mRNA metabolism, cell fate transitions, and stress granule/P-body dynamics. Its role in various disease conditions such as inflammatory diseases and pancreatic cancer, as revealed by loss-of-function experiments, highlights its potential as a therapeutic target. Understanding DDX6 function through genetic models like KO or CKO mouse models can provide insights into disease mechanisms and potential treatment strategies.

References:

1. Di Stefano, Bruno, Luo, En-Ching, Haggerty, Chuck, Yeo, Gene W, Hochedlinger, Konrad. 2019. The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis. In Cell stem cell, 25, 622-638.e13. doi:10.1016/j.stem.2019.08.018. https://pubmed.ncbi.nlm.nih.gov/31588046/

2. Ripin, Nina, Macedo de Vasconcelos, Luisa, Ugay, Daniella A, Parker, Roy. 2024. DDX6 modulates P-body and stress granule assembly, composition, and docking. In The Journal of cell biology, 223, . doi:10.1083/jcb.202306022. https://pubmed.ncbi.nlm.nih.gov/38536035/

3. Weber, Ramona, Chang, Chung-Te. 2024. Human DDX6 regulates translation and decay of inefficiently translated mRNAs. In eLife, 13, . doi:10.7554/eLife.92426. https://pubmed.ncbi.nlm.nih.gov/38989862/

4. Ostareck, Dirk H, Naarmann-de Vries, Isabel S, Ostareck-Lederer, Antje. 2014. DDX6 and its orthologs as modulators of cellular and viral RNA expression. In Wiley interdisciplinary reviews. RNA, 5, 659-78. doi:10.1002/wrna.1237. https://pubmed.ncbi.nlm.nih.gov/24788243/

5. Naito, Seiichiro, Tanaka, Hiroki, Jiang, Jing-Jing, Hashimoto, Shigeru, Murakami, Masaaki. 2024. DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation. In Biochemical and biophysical research communications, 703, 149666. doi:10.1016/j.bbrc.2024.149666. https://pubmed.ncbi.nlm.nih.gov/38377944/

6. Deng, Xin, Liu, Zhen, Wang, Baosheng, Ma, Jia, Meng, Xiangpeng. . The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38, e23581. doi:10.1096/fj.202400166R. https://pubmed.ncbi.nlm.nih.gov/38551642/