Skip to main content
. 2020 Mar 10;9(3):672. doi: 10.3390/cells9030672

Figure 3.

Figure 3

Gcn2 and Yih1p/IMPACT activity is controlled via spatiotemporally constrained rearrangements of the actin cytoskeleton. (A) Interactions preventing Gcn2 activation and thus resulting in high rates of protein synthesis. In the current working model, eEF1A binds to Gcn2 to prevent its stimulation. Low G-actin levels dissociate Yih1/IMPACT from actin and Yih1/IMPACT then binds to Gcn1, thereby preventing Gcn1 from activating Gcn2. Current findings suggest that this is due to its inability to promote transfer of the starvation signal (uncharged tRNAs, i.e., tRNAdeacyl) to Gcn2. Yih1/IMPACT released from actin would allow Yih1/IMPACT to also execute Gcn2-independent functions. Increased de novo synthesis of eEF1A, and/or its augmented release from F-actin, enhances eEF1A binding to Gcn2 to prevent its activation. (B) Interactions promoting Gcn2 activation and eIF2α phosphorylation by Gcn2 to dampen global protein synthesis and enhance translation of specific mRNAs. Uncharged tRNAs (tRNAdeacyl) abrogate Gcn2-eEF1A interaction, allowing Gcn2 activation. Enhanced eEF1A interaction with F-actin may also favor dissociation of eEF1A from Gcn2. Actin depolymerization increases the levels of G-actin, which then sequesters Yih1/IMPACT. Sequestration of Yih1/IMPACT allows enhanced Gcn1-Gcn2 interaction, which in turn enhances Gcn2 sensitivity to tRNAdeacyl. Actin depolymerization leads to increased levels of tRNAdeacyl and this further contributes to the activation of Gcn2. Enhanced Gcn2 activity and eIF2α phosphorylation lead to attenuation of global protein synthesis and concomitant enhancement of the expression of Gcn4/ATF4. These major transcriptional regulators adjust the gene expression profile in response to the activating cue that was imposed on the cell. (C) Simple schematic showing the domains of Gcn1, Gcn2 and IMPACT and the protein regions known so far to be involved in protein-protein interactions that stimulate or inhibit Gcn2. For simplicity, the ribosome has been omitted in this figure and instead protein regions involved in interactions with the ribosome are shown with a cyan shadow.