Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
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| Abstract |
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.
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| Authors | Laura Hinze, Sabine Schreek, Andre Zeug, Nurul Khalida Ibrahim, Beate Fehlhaber, Lorent Loxha, Buesra Cinar, Evgeni Ponimaskin, James Degar, Connor McGuckin, Gabriela Chiosis, Cornelia Eckert, Gunnar Cario, Beat Bornhauser, Jean-Pierre Bourquin, Martin Stanulla, Alejandro Gutierrez |
| Journal | Molecular cell (Mol Cell) Vol. 82 Issue 15 Pg. 2858-2870.e8 (08 04 2022) ISSN: 1097-4164 [Electronic] United States |
| PMID | 35732190 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2022 Elsevier Inc. All rights reserved. |
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