Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12

• Published in: Cell death & disease Vol. 2; no. 4; p. e149
• Main Authors: Badiola, N, Penas, C, Miñano-Molina, A, Barneda-Zahonero, B, Fadó, R, Sánchez-Opazo, G, Comella, J X, Sabriá, J, Zhu, C, Blomgren, K, Casas, C, Rodríguez-Alvarez, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2011; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/80/642/1463; 631/80/82/23; 631/80/86; Activating Transcription Factor 4 - metabolism; Animals; Animals, Newborn; Antibodies; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Biochemistry; Biomedical and Life Sciences; Calpain - metabolism; Caspase 12 - metabolism; Cell Biology; Cell Culture; Cell Culture Techniques; Cell Hypoxia; Cells, Cultured; Cerebral Cortex - cytology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; eIF-2 Kinase - metabolism; Endoplasmic Reticulum - physiology; Enzyme Activation; Eukaryotic Initiation Factor-2 - metabolism; Glucose - deficiency; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Immunology; Life Sciences; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; Membrane Proteins - genetics; Membrane Proteins - metabolism; Original; original-article; Protein Biosynthesis; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - metabolism; Regulatory Factor X Transcription Factors; Signal Transduction; Stress, Physiological; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation; X-Box Binding Protein 1; apoptosis; caspase-12; brain; cell culture; endoplasmic reticulum stress; ischemia
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2011.31

Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia–ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2
α
, an increase in ATF4 levels and the induction of
gadd34
(a subunit of an eIF2
α
-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of
xbp1
, which would be responsible for the observed expression of
edem2
and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.