Nitric oxide contributes to protein homeostasis by S-nitrosylations of the chaperone HSPA8 and the ubiquitin ligase UBE2D.
Autophagy
Cell Cycle
Cell Line
Cell Proliferation
Cellular Senescence
Cysteine
/ metabolism
HSC70 Heat-Shock Proteins
/ metabolism
Humans
Lysosomes
/ metabolism
Molecular Chaperones
/ metabolism
Nitric Oxide
/ metabolism
Oxidation-Reduction
/ drug effects
Proteome
Proteostasis
/ drug effects
Sirolimus
/ pharmacology
Ubiquitin-Conjugating Enzymes
/ metabolism
Ubiquitination
/ drug effects
Autophagy
Chaperone
Lysosome
Nitric oxide
Posttranslational modification
Rapamycin
Redox modification
Senescence
Starvation
Ubiquitin
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
28
07
2018
revised:
25
09
2018
accepted:
02
10
2018
pubmed:
28
10
2018
medline:
22
3
2019
entrez:
28
10
2018
Statut:
ppublish
Résumé
Upregulations of neuronal nitric oxide synthase (nNOS) in the rodent brain have been associated with neuronal aging. To address underlying mechanisms we generated SH-SY5Y neuronal cells constitutively expressing nNOS at a level similar to mouse brain (nNOS+ versus MOCK). Initial experiments revealed S-nitrosylations (SNO) of key players of protein homeostasis: heat shock cognate HSC70/HSPA8 within its nucleotide-binding site, and UBE2D ubiquitin conjugating enzymes at the catalytic site cysteine. HSPA8 is involved in protein folding, organelle import/export and chaperone-mediated LAMP2a-dependent autophagy (CMA). A set of deep redox and full proteome analyses, plus analysis of autophagy, CMA and ubiquitination with rapamycin and starvation as stimuli confirmed the initial observations and revealed a substantial increase of SNO modifications in nNOS+ cells, in particular targeting protein networks involved in protein catabolism, ubiquitination, carbohydrate metabolism and cell cycle control. Importantly, NO-independent reversible oxidations similarly occurred in both cell lines. Functionally, nNOS caused an accumulation of proteins, including CMA substrates and loss of LAMP2a. UBE2D activity and proteasome activity were impaired, resulting in dysregulations of cell cycle checkpoint proteins. The observed changes of protein degradation pathways caused an expansion of the cytoplasm, large lysosomes, slowing of the cell cycle and suppression of proliferation suggesting a switch of the phenotype towards aging, supported by downregulations of neuronal progenitor markers but increase of senescence-associated proteins. Hence, upregulation of nNOS in neuronal cells imposes aging by SNOing of key players of ubiquitination, chaperones and of substrate proteins leading to interference with crucial steps of protein homeostasis.
Identifiants
pubmed: 30368041
pii: S2213-2317(18)30664-5
doi: 10.1016/j.redox.2018.10.002
pmc: PMC6202877
pii:
doi:
Substances chimiques
HSC70 Heat-Shock Proteins
0
HSPA8 protein, human
0
Molecular Chaperones
0
Proteome
0
Nitric Oxide
31C4KY9ESH
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Cysteine
K848JZ4886
Sirolimus
W36ZG6FT64
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
217-235Informations de copyright
Copyright © 2018. Published by Elsevier B.V.
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