DDX6 and its orthologs as modulators of cellular and viral RNA expression

Abstract

DDX6 (Rck/p54), a member of the DEAD-box family of helicases, is highly conserved from unicellular eukaryotes to vertebrates. Functions of DDX6 and its orthologs in dynamic ribonucleoproteins contribute to global and transcript-specific messenger RNA (mRNA) storage, translational repression, and decay during development and differentiation in the germline and somatic cells. Its role in pathways that promote mRNA-specific alternative translation initiation has been shown to be linked to cellular homeostasis, deregulated tissue development, and the control of gene expression in RNA viruses. Recently, DDX6 was found to participate in mRNA regulation mediated by miRNA-mediated silencing. DDX6 and its orthologs have versatile functions in mRNA metabolism, which characterize them as important post-transcriptional regulators of gene expression.

DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes

“…We chose DDX6 (p = 8.67E-15) and USP14 (p = 1.22E-12) for validation and follow-up experiments based on their statistical ranking and literature indicating that their proteins may play a role in ISG regulation. DDX6 encodes the decapping coactivator, DEAD-box helicase 6, which localizes to processing bodies (P-bodies) where it plays a central role in RNA metabolism (Ostareck et al, 2014). Other members of the DExD/H-box helicase family play crucial roles in ISG regulation, such as the RNA-sensors, RIG-I and MDA5 (Fullam and Schröder, 2013).…”

“…DDX6 is a key regulator of RNA metabolism and formation of P-bodies, which are sites of mRNA storage and decay (Andrei et al, 2005; Ayache et al, 2015; Chu and Rana, 2006; Ostareck et al, 2014). Aberrant RNA metabolism can inadvertently trigger PRRs via the accumulation of self nucleic acids.…”

Regulation of global and specific mRNA translation by the mTOR signaling pathway

“…DDX6 (also known as RCK or p54) is a highly conserved DEAD-box helicase that contributes to global and transcript-specific mRNA storage, translational repression, and decay. 101 Recently, DDX6 was found to participate in the miRNA-mediated silencing of specific transcripts, 102 suggesting that in this case mTOR may participate in the translational repression of DDX6-bound transcripts. The highly conserved protein DHX9 (also known as RNA helicase A; RHA) was also recognized to participate in translation initiation.…”

Conserved abundance and topological features in chromatin‐remodeling protein interaction networks

“…Also, the human forms of these three proteins also have strong links to disease. For instance, mutations in the hPICALM gene have been implicated in oncogenesis [32], PICALM is implicated in Alzheimer's disease [33], TPT1 is implicated in tumorigenesis [34], and DDX6 is involved in gene expression in RNA viruses like HIV [35]. Of these, yeast two hybrid analysis has linked TPT1 to the SWI/SNF complex [36], providing support for our results that these proteins not only form a subnetwork among themselves but have intriguing links to chromatin remodeling that warrants further study.…”