The antibiotic robenidine exhibits guanabenz-like cytoprotective properties by a mechanism independent of protein phosphatase PP1:PPP1R15A.
J Biol Chem
; 294(36): 13478-13486, 2019 09 06.
Article
em En
| MEDLINE
| ID: mdl-31337709
ABSTRACT
The aminoguanidine compound robenidine is widely used as an antibiotic for the control of coccidiosis, a protozoal infection in poultry and rabbits. Interestingly, robenidine is structurally similar to guanabenz (analogs), which are currently undergoing clinical trials as cytoprotective agents for the management of neurodegenerative diseases. Here we show that robenidine and guanabenz protect cells from a tunicamycin-induced unfolded protein response to a similar degree. Both compounds also reduced the tumor necrosis factor α-induced activation of NF-κB. The cytoprotective effects of guanabenz (analogs) have been explained previously by their ability to maintain eIF2α phosphorylation by allosterically inhibiting protein phosphatase PP1PPP1R15A. However, using a novel split-luciferase-based protein-protein interaction assay, we demonstrate here that neither robenidine nor guanabenz disrupt the interaction between PPP1R15A and either PP1 or eIF2α in intact cells. Moreover, both drugs also inhibited the unfolded protein response in cells that expressed a nonphosphorylatable mutant (S51A) of eIF2α. Our results identify robenidine as a PP1PPP1R15A-independent cytoprotective compound that holds potential for the management of protein misfolding-associated diseases.
Palavras-chave
bioluminescence; biosensor; cell proliferation; drug action; eIF2; endoplasmic reticulum stress (ER stress); enzyme inhibitor; guanabenz; neurodegenerative disease; protein phosphatase; protein phosphatase 1 (PP1); protein phosphatase 1 regulatory subunit 15A (PPP1R15A); robenidine; unfolded protein response (UPR)
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Robenidina
/
Receptores de Neuropeptídeo Y
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Substâncias Protetoras
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Proteína Fosfatase 1
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Antibacterianos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article