Supramolecular assembly of GSK3α as a cellular response to amino acid starvation

The tolerance of amino acid starvation is fundamental to robust cellular fitness. Asparagine depletion is lethal to some cancer cells, a vulnerability that can be exploited clinically. We report that resistance to asparagine starvation is uniquely dependent on an N-terminal low-complexity domain of GSK3 alpha, which its paralog GSK3 beta lacks. In response to depletion of specific amino acids, including asparagine, leucine, and valine, this domain mediates supramolecular assembly of GSK3 alpha with ubiquitin-proteasome system components in spatially sequestered cytoplasmic bodies. This effect is independent of mTORC1 or GCN2. In normal cells, GSK3 alpha promotes survival during essential amino acid starvation. In human leukemia, GSK3 alpha body formation predicts asparaginase resistance, and sensitivity to asparaginase combined with a GSK3 alpha inhibitor. We propose that GSK3 alpha body formation provides a cellular mechanism to maximize the catalytic efficiency of proteasomal protein degradation in response to amino acid starvation, an adaptive response co-opted by cancer cells for asparaginase resistance.

Automated summary

The tolerance of amino acid starvation is crucial for cellular fitness. A study found that resistance to asparagine starvation depends on a low-complexity domain in GSK3 alpha, but not in its paralog GSK3 beta. This domain mediates the assembly of GSK3 alpha with components of the ubiquitin-proteasome system in response to amino acid depletion. The formation of these assemblies, known as GSK3 alpha bodies, maximizes the efficiency of proteasomal protein degradation and is associated with asparaginase resistance in leukemia.