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

Amino Acids / metabolism Asparaginase / genetics Asparagine Humans Leukemia Protein Serine-Threonine Kinases
GSK3 Wnt asparaginase protein degradation ubiquitin-proteasome system

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
04 08 2022
Historique:
received: 01 02 2021
revised: 13 04 2022
accepted: 20 05 2022
pubmed: 23 6 2022
medline: 10 8 2022
entrez: 22 6 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.molcel.2022.05.025 PMID: 35732190 PMC: PMC9357031
pubmed: 35732190
pii: S1097-2765(22)00492-0
doi: 10.1016/j.molcel.2022.05.025
pmc: PMC9357031
mid: NIHMS1811965
pii:
doi:

Substances chimiques

Amino Acids 0
Asparagine 7006-34-0
Protein Serine-Threonine Kinases EC 2.7.11.1
Asparaginase EC 3.5.1.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2858-2870.e8

Subventions

Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193651
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA249678
Pays : United States

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests Boston Children’s Hospital has filed patents on the subject matter of this manuscript. G.C. is a founder of Samus Therapeutics and a member of its board of directors. A.G. is on a scientific advisory board for Attivare Therapeutics and receives research funding from Astellas Pharma.

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Auteurs

Laura Hinze (L)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany. Electronic address: hinze.laura@mh-hannover.de.

Sabine Schreek (S)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.

Andre Zeug (A)

Department of Cellular Neurophysiology, Hannover Medical School, Hannover 30625, Germany.

Nurul Khalida Ibrahim (NK)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.

Beate Fehlhaber (B)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.

Lorent Loxha (L)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.

Buesra Cinar (B)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.

Evgeni Ponimaskin (E)

Department of Cellular Neurophysiology, Hannover Medical School, Hannover 30625, Germany.

James Degar (J)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Connor McGuckin (C)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Gabriela Chiosis (G)

Chemical Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.

Cornelia Eckert (C)

Department of Pediatric Hematology and Oncology, Charité Universitätsmedizin, Berlin, Berlin 10117, Germany.

Gunnar Cario (G)

Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel 21405, Germany.

Beat Bornhauser (B)

Department of Pediatric Hematology/Oncology, University Children's Hospital, Zurich 8032, Switzerland.

Jean-Pierre Bourquin (JP)

Department of Pediatric Hematology/Oncology, University Children's Hospital, Zurich 8032, Switzerland.

Martin Stanulla (M)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.

Alejandro Gutierrez (A)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: alejandro.gutierrez@childrens.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Supramolecular assembly of GSK3α as a cellular...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Amidohydrolases › Asparaginase › Supramolecular assembly of GSK3α as a cellular...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Asparagine › Supramolecular assembly of GSK3α as a cellular...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Supramolecular assembly of GSK3α as a cellular...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › Supramolecular assembly of GSK3α as a cellular...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Supramolecular assembly of GSK3α as a cellular...