Protein synthesis is mainly regulated by phosphorylation of the eukaryotic translation initiation factor eIF2, which is mediated by four kinases in mammals, including the amino-acid-sensor GCN2. This allows cells to quickly adapt to external and internal cues. The integrity of the actin cytoskeleton has been suggested to modulate translation, but the underlying mechanisms are poorly understood. In this study (p. 4521), Beatriz Castilho and colleagues now investigate how perturbation of F-actin affects translation. They observe that depolymerisation of F-actin in mouse cells inhibits protein synthesis in a GCN2-dependent manner and results in increased levels of uncharged tRNA, indicative of a direct effect of GCN2. The authors then show that GCN2 is found in two complexes, one with GCN1 and another with the eukaryotic elongation factor 1A (eEF1A). Upon actin depolymerisation, the abundance of the former complex increases while that of the latter complex decreases; this shift is possibly mediated by a release of GCN1 from its ligand IMPACT, a G-actin-interacting protein. The increase in the amount of GCN2–GCN1 complexes then sensitizes GCN2 for its activating ligand, uncharged tRNAs. This study thus points to a crosstalk between the cytoskeleton and translation that is mediated by GCN2, a mechanism that could also allow for a spatiotemporal regulation of protein synthesis in response to dynamic or local changes in the balance between actin monomers and filaments.
