Wnt signalling antagonizes stress granule assembly through a Dishevelled-dependent mechanism

Abstract

SummaryCells often respond to diverse environmental stresses by inducing stress granules (SGs) as an adaptive mechanism. SGs are generally assembled as a result of aggregation of mRNAs stalled in a translational pre-initiation complex, mediated by a set of RNA-binding proteins such as G3BP and TIA-1. SGs may serve as triage centres for storage, translation re-initiation or degradation of specific mRNAs. However, the mechanism involved in the modulation of their assembly/disassembly is unclear. Here we report that Wnt signalling negatively regulates SG assembly through Dishevelled (Dvl), a cytoplasmic Wnt effector. Overexpression of Dvl2, an isoform of Dvl, leads to impairment of SG assembly through a DEP domain dependent mechanism. Intriguingly, the Dvl2 mutant K446M, which corresponds to an analogous mutation in Drosophila Dishevelled DEP domain (dsh1) that results in defective PCP pathway, fails to antagonize SG assembly. Furthermore, we show that Dvl2 exerts the antagonistic effect on SG assembly through a mechanism involving Rac1-mediated inhibition of RhoA. Dvl2 interacts with G3BP, a downstream component of Ras signalling involved in SG assembly, and functional analysis suggests a model wherein the Dvl-Rac1-RhoA axis regulates G3BP's SG-nucleating activity. Collectively, these results define an antagonistic effect of Wnt signalling on SG assembly, and reveal a novel role for Wnt/Dvl pathway in the modulation of mRNA functions.

Stress granules and cell signaling: more than just a passing phase?

“…In NIH3T3 cells, Wnt signaling triggers Dvl-dependent activation of the Rac1 GTPase. Activated Rac1, in turn, inactivates the RhoA GTPase to inhibit SG assembly 67 . Thus, Wnt signaling antagonizes SG assembly.…”

Nup358 binds to AGO proteins through its SUMO ‐interacting motifs and promotes the association of target mRNA with miRISC

“…The images were acquired using ImageQuant LAS 4000 (GE Healthcare). EZview TM Red Anti-HA Affinity beads (Sigma) and rabbit GFP antibody [86]-bound protein A beads (Invitrogen) were used for immunoprecipitation of HA-and GFPtagged proteins, respectively.…”

“…Rabbit anti-GFP (1:10,000) and rabbit anti-Nup358 (1:3,000) antibodies have been described earlier [25,86].…”

Zebrafish P54 RNA helicases are cytoplasmic granule residents that are required for development and stress resilience

“…We looked for a relationship between the function of stress granules and somite development in zebrafish and found that P97a and P97b, homologous proteins to the translation initiation factor eIF4G, are components of stress granules and both are required in zebrafish for mesoderm formation (Nousch et al, 2007). At the same time we found that the mammalian Disheveled (Dvl) protein, an effector of the Wnt signaling pathway, negatively regulates the assembly of stress granules (Sahoo et al, 2012) and it is known that the Wnt pathway is involved in zebrafish somite formation (Bajard et al, 2014). …”

“…Important reservoirs for mRNAs are the RNA granules, which include P-bodies (Oh et al, 2013; Parker and Sheth, 2007), stress granules (Anderson and Kedersha, 2008; Kedersha et al, 2002; Sahoo et al, 2012), germ granules (in germ cells) (Updike and Strome, 2010), and other types of RNA-containing cytoplasmic foci. This classification of RNA granules is based on their composition, size and cell of origin.…”