The GCN2/eIF2αK stress kinase regulates PP1 to ensure mitotic fidelity

GCN2/eIF2 alpha K4 is exclusively seen as an eIF2 alpha kinase, which regulates reprogramming of protein translation in response to stress. Here, we show that GCN2 has an unexpected role in unstressed cells as a regulator of mitosis. This function is not through its canonical role in translation reprogramming, but through the regulation of two previously unidentified substrates, PP1 alpha and gamma. In the absence of GCN2 function, timing and levels of phosphorylation of key mitotic players are altered, leading to aberrant chromosome alignment, missegregating chromosomes, elevated number of tripolar spindles, and a delay in progression through mitosis. Pharmacological inhibition of GCN2 results in similar effects and is synergistic with Aurora A inhibition in causing more severe mitotic errors and cell death. We suggest that GCN2-dependent phosphorylation of PP1 alpha and gamma restrains their activity and this is important to ensure the timely regulation of phosphorylation of several PP1 substrates during early mitosis. These findings highlight a druggable PP1 inhibitor and open new avenues of research on the therapeutic potential of GCN2 inhibitors.

Automated summary

GCN2/eIF2 alpha K4 serves as an eIF2 alpha kinase in stress response and unexpectedly acts as a regulator of mitosis in unstressed cells. Its function in mitosis is not related to translation reprogramming, but through the regulation of PP1 alpha and gamma, which were previously unidentified substrates. Inhibition of GCN2 or Aurora A leads to mitotic errors and cell death, suggesting the potential therapeutic utility of GCN2 inhibitors. These findings provide insights into the timely regulation of phosphorylation events during early mitosis.