Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis.
GCLC
NRF2
cysteine
cystine
ferroptosis
glutamate
γ-glutamyl
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
05 01 2021
05 01 2021
Historique:
received:
02
06
2020
revised:
09
10
2020
accepted:
08
12
2020
pubmed:
29
12
2020
medline:
30
11
2021
entrez:
28
12
2020
Statut:
ppublish
Résumé
Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation.
Identifiants
pubmed: 33357455
pii: S1550-4131(20)30662-8
doi: 10.1016/j.cmet.2020.12.007
pmc: PMC7839835
mid: NIHMS1655933
pii:
doi:
Substances chimiques
GCLC protein, human
EC 6.3.2.2
Glutamate-Cysteine Ligase
EC 6.3.2.2
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
174-189.e7Subventions
Organisme : NCI NIH HHS
ID : R01 CA189623
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA230042
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI148118
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123738
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests I.S.H. is a consultant for Ono Pharma USA. E.S. is an inventor of intellectual property related cyst(e)inase, and has an equity interest in Aeglea Biotherapeutics, a company pursuing the commercial development of cyst(e)inase. These companies had no role in funding or the design of this study.
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