DDX3 Participates in Translational Control of Inflammation Induced by Infections and Injuries

Abstract

Recent studies have suggested that DDX3 functions in antiviral innate immunity, but the underlying mechanism remains elusive. We previously identified target mRNAs whose translation is controlled by DDX3. Pathway enrichment analysis of these targets indicated that DDX3 is involved in various infections and inflammation. Using immunoblotting, we confirmed that PACT, STAT1, GNB2, Rac1, TAK1, and p38 mitogen-activated protein kinase (MAPK) proteins are downregulated by DDX3 knockdown in human monocytic THP-1 cells and epithelial HeLa cells. Polysome profiling revealed that DDX3 knockdown reduces the translational efficiency of target mRNAs. We further demonstrated DDX3-mediated translational control of target mRNAs by luciferase reporter assays. To examine the effects of DDX3 knockdown on macrophage migration and phagocytosis, we performed in vitro cell migration assay and flow cytometry analysis of the uptake of green fluorescent protein-expressing Escherichia coli in THP-1 cells. The DDX3 knockdown cells exhibited impaired macrophage migration and phagocytosis. Moreover, we used a human cytokine antibody array to identify the cytokines affected by DDX3 knockdown. Several chemokines were decreased considerably in DDX3 knockdown THP-1 cells after lipopolysaccharide or poly(I·C) stimulation. Lastly, we demonstrated that DDX3 is crucial for the recruitment of phagocytes to the site of inflammation in transgenic zebrafish.

The Drosophila RNA Helicase Belle (DDX3) Non-Autonomously Suppresses Germline Tumorigenesis Via Regulation of a Specific mRNA Set

“…This indicates that Belle interacts predominantly with mature mRNAs and preferentially acts as a translational regulator. In accordance with previously published data, Belle/DDX3 can be involved both in translational repression and translational activation of target transcripts [18,[26][27][28][73][74][75][76]. Our CLIP-seq analysis provides entry points in attempting to understand the molecular mechanisms underlying the spermatogenesis defects observed in both in somatic cyst cells and in the germline with failures of Belle expression.…”

Inhibition of the Dead Box RNA Helicase 3 prevents HIV-1 Tat and cocaine-induced neurotoxicity by targeting microglia activation

“…The direct role of DDX3 in regulating pro-inflammatory responses in the pathogenesis of bowel disease and Listeria infection were also recently observed (62,63). Inhibition of DDX3 activity stalled the translation of target proteins (38,64), resulting in a decrease of cytokine secretion and inhibition of macrophage migration and phagocytosis (38). It therefore appears plausible that DDX3-dependent translational control may be the mechanism that regulates microglial activation in neuroinflammatory pathways.…”

“…These pathways are well known to control the inflammatory response, cytokine secretion, and migration of macrophages. Importantly, it was recently shown that DDX3 directly regulates the translation of p38 MAPK, Rac1, STAT1 (TGFβ) and TAK1, which play essential roles in NF-κB regulation (38). The direct role of DDX3 in regulating pro-inflammatory responses in the pathogenesis of bowel disease and Listeria infection were also recently observed (62,63).…”

The RNA helicase DDX3 induces neural crest by promoting AKT activity

“…The RNA helicase activity of DDX3 is needed for the efficient translation of certain mRNAs with highly structured 5'-UTR (Guenther et al, 2018;Sen et al, 2015). A known direct target of DDX3 in mammals is RAC1 (Chen et al, 2015;Chen et al, 2016;Ku et al, 2018), which is extremely conserved throughout vertebrate evolution (100% identical between human and X. tropicalis orthologs). Interestingly, mutations in RAC1 cause craniofacial disorders and other potential NC and CNS defects, which are highly similar to those caused by DDX3X mutations (Reijnders et al, 2017).…”

“…can promote translational initiation of mRNAs with long and structured 5'-UTR through its RNA helicase activity, a function that is conserved from yeast to humans (Guenther et al, 2018;Sen et al, 2015). One of these mRNAs encodes RAC1, which can mediate DDX3 function in other physiological processes in mammals (Chen et al, 2015;Chen et al, 2016;Ku et al, 2018). Notably, RAC1 can activate AKT through its downstream effector p21-activated kinase (PAK) (Higuchi et al, 2008).…”