Protein phosphatase 1 regulates reactive oxygen species-dependent degradation of histone deacetylase 5 by intermittent hypoxia.
Am J Physiol Cell Physiol
; 323(2): C423-C431, 2022 08 01.
Article
en En
| MEDLINE
| ID: mdl-35704695
We recently reported pheochromocytoma 12 (PC12) cells and rats subjected to intermittent hypoxia (IH), a hallmark manifestation of obstructive sleep apnea (OSA), exhibit reduced histone deacetylase activity and HDAC5 protein. Our study further suggested that posttranslational modifications rather than transcriptional mechanism(s) mediate IH-induced HDAC5 degradation. These observations prompted our current study to investigate the mechanism(s) underlying HDAC5 degradation by IH in PC12 cell cultures. IH-induced HDAC5 degradation was blocked by an antioxidant, and reactive oxygen species (ROS) mimetics decreased HDAC5 protein, suggesting that ROS mediates HDAC5 degradation by IH. NADPH oxidases (NOX) 2 and 4 were identified as sources of ROS that mediate the effects of IH. HDAC5 degradation during IH was associated with dephosphorylation of HDAC5 at serine259, and this response was blocked by a NOX inhibitor, suggesting that ROS-dependent dephosphorylation mediates HDAC5 degradation. IH-induced dephosphorylation of HDCA5 was inhibited by calyculin A, an inhibitor of protein phosphatase (PP)-1 and -2, or by the overexpression of nuclear inhibitor of PP1 (NIPP1). HDAC5 dephosphorylation by IH lead to augmented hypoxia-inducible factor (HIF)-1α protein and an increase in its transcriptional activity. These data suggest that PP1-dependent dephosphorylation of S259 destabilizes HDAC5 protein in response to IH, resulting in HIF-1α stabilization and transcriptional activity. Our findings highlight hither to unexplored role of protein phosphatases, especially PP1 in regulating HDAC5 protein, which is an upstream activator of HIF-1 signaling by IH.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína Fosfatasa 1
/
Histona Desacetilasas
/
Hipoxia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Am J Physiol Cell Physiol
Asunto de la revista:
FISIOLOGIA
Año:
2022
Tipo del documento:
Article
Pais de publicación:
Estados Unidos