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Critical loss of CBP/p300 histone acetylase activity by caspase‐6 during neurodegeneration
Author(s) -
Rouaux Caroline,
Jokic Natasa,
Mbebi Corinne,
Boutillier Stephanie,
Loeffler JeanPhilippe,
Boutillier AnneLaurence
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg615
Subject(s) - creb , biology , neurodegeneration , neuroprotection , histone acetyltransferases , creb binding protein , histone , acetylation , microbiology and biotechnology , p300 cbp transcription factors , caspase , caspase 2 , chromatin , apoptosis , neuroscience , programmed cell death , transcription factor , biochemistry , medicine , dna , disease , gene
By altering chromatin structure, histone acetyltransferases (HATs) act as transcriptional regulators. We observed in a model of primary neurons that histone acetylation levels decreased at the onset of apoptosis. The CREB‐binding protein (CBP) is a HAT of particular interest because it also acts as a co‐activator controlling, among others, CREB‐dependent transcriptional activity. It has been demonstrated that CREB exerts neuroprotective functions, but the fate of CBP during neuronal apoptosis remained unclear till now. This work provided evidence that CBP is specifically targeted by caspases and calpains at the onset of neuronal apoptosis, and CBP was futher identified as a new caspase‐6 substrate. This ultimately impinged on the CBP/p300 HAT activity that decreased with time during apoptosis entry, whereas total cellularHAT activity remained unchanged. Interestingly, CBP loss and histone deacetylation were observed in two different pathological contexts: amyloid precursor protein‐dependent signaling and amyotrophic lateralsclerosis model mice, indicating that these modifications are likely to contribute to neurodegenerative diseases. In terms of function, we demonstrated that fine‐tuning of CBP HAT activity is necessary to ensure neuroprotection.