Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
复制标题
GSK3α的超分子组装作为氨基酸饥饿的细胞反应。
DOI：
10.1016/j.molcel.2022.05.025
复制
发表时间：
2022-08-04
期刊：
影响因子：
16
通讯作者：
Gutierrez, Alejandro
中科院分区：
文献类型：
--
作者：
Hinze, Laura;Schreek, Sabine;Zeug, Andre;Ibrahim, Nurul Khalida;Fehlhaber, Beate;Loxha, Lorent;Cinar, Buesra;Ponimaskin, Evgeni;Degar, James;McGuckin, Connor;Chiosis, Gabriela;Eckert, Cornelia;Cario, Gunnar;Bornhauser, Beat;Bourquin, Jean-Pierre;Stanulla, Martin;Gutierrez, Alejandro
对氨基酸饥饿的耐受性是强健的细胞适应性的基础。天冬酰胺耗尽对某些癌细胞是致命的，临床上使用天冬酰胺酶利用了这一弱点。我们报道，对天冬酰胺饥饿的抗性是唯一依赖于其副产物GSK 3 β中缺乏的GSK 3 α的N-末端低复杂性结构域。响应于特定氨基酸（包括天冬酰胺、亮氨酸或缬氨酸）的消耗，该结构域介导GSK 3 α与空间隔离的胞质体中的泛素-蛋白酶体系统组分的超分子组装。这种效应不依赖于mTORC 1或GCN 2。在正常细胞中，GSK 3 α在必需氨基酸饥饿期间促进存活。在人类白血病中，GSK 3 α小体的形成预示着天冬酰胺酶耐药，以及对天冬酰胺酶联合GSK 3 α抑制剂的敏感性。我们认为，GSK 3 α体的形成提供了一种细胞机制，以最大限度地提高蛋白酶体蛋白降解的催化效率，以响应氨基酸饥饿，一种适应性反应，由癌细胞选择天冬酰胺酶抗性。Hinze等表明，天冬酰胺酶抗性依赖于GSK 3 α的N-末端低复杂性结构域，而GSK 3 β的N-末端低复杂性结构域缺乏。作为对氨基酸饥饿的适应性反应，GSK 3 α与泛素蛋白酶体系统组分进行超分子组装以促进蛋白质降解，这是氨基酸的替代来源。
The tolerance of amino acid starvation is fundamental to robust cellular fitness. Asparagine depletion is lethal to some cancer cells, a vulnerability exploited clinically using asparaginase. We report that resistance to asparagine starvation is uniquely dependent on an N-terminal low-complexity domain of GSK3α lacking in its paralog GSK3β. In response to depletion of specific amino acids, including asparagine, leucine or 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. Hinze et al. show that asparaginase resistance is dependent on an N-terminal low complexity domain of GSK3α lacking in its paralog GSK3β. As an adaptive response to amino acid starvation, GSK3α undergoes supramolecular assembly with ubiquitin proteasome system components to promote protein degradation, an alternative source of amino acids.
登录
查看更多内容
影响因子：
14.9
作者：
NCBI Resource Coordinators
通讯作者：
NCBI Resource Coordinators
影响因子：
16
作者：
Dao TP;Kolaitis RM;Kim HJ;O'Donovan K;Martyniak B;Colicino E;Hehnly H;Taylor JP;Castañeda CA
通讯作者：
Castañeda CA
DOI：
10.1073/pnas.1423533112
发表时间：
2015-05-05
影响因子：
11.1
作者：
Huang, Ya-Lin;Anvarian, Zeinab;Niehrs, Christof
通讯作者：
Niehrs, Christof
影响因子：
20.3
作者：
Appel, Inge M.;den Boer, Monique L.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
11.8
作者：
Doble, Bradley W.;Patel, Satish;Woodgett, James R.
通讯作者：
Woodgett, James R.