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 GSK3α, which its paralog GSK3β lacks. In response to depletion of specific amino acids, including asparagine, leucine, and valine, this domain mediates supramolecular assembly of GSK3α with ubiquitin-proteasome system components in spatially sequestered cytoplasmic bodies. This effect is independent of mTORC1 or GCN2. In normal cells, GSK3α promotes survival during essential amino acid starvation. In human leukemia, GSK3α body formation predicts asparaginase resistance, and sensitivity to asparaginase combined with a GSK3α inhibitor. We propose that GSK3α 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.

氨基酸饥饿的耐受性是细胞健康的基础。天冬酰胺的消耗对某些癌细胞来说是致命的，这是一个可以在临床上利用的漏洞。我们报告说，对天冬酰胺饥饿的抵抗唯一依赖于 GSK3α 的 N 端低复杂性结构域，而其旁系同源物 GSK3β 则缺乏该结构域。为了响应天冬酰胺、亮氨酸和缬氨酸等特定氨基酸的耗尽，该结构域介导 GSK3α 与泛素蛋白酶体系统组件在空间隔离的细胞质体中进行超分子组装。该效应与 mTORC1 或 GCN2 无关。在正常细胞中，GSK3α 可促进必需氨基酸饥饿期间的存活。在人类白血病中，GSK3α 体的形成可预测天冬酰胺酶耐药性以及对天冬酰胺酶与 GSK3α 抑制剂联合使用的敏感性。我们认为，GSK3α 体的形成提供了一种细胞机制，可以最大限度地提高蛋白酶体蛋白降解的催化效率，以应对氨基酸饥饿，这是癌细胞对天冬酰胺酶耐药性的适应性反应。