Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration.
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 cellular HAT activity remained unchanged. Interestingly, CBP loss and histone deacetylation were observed in two different pathological contexts: amyloid precursor protein-dependent signaling and amyotrophic lateral sclerosis 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.
Rouaux
Caroline
C
Laboratoire de Signalisation Moléculaire et Neurodégénérescence-EA 3433, 11 rue Humann, 67085 Strasbourg cedex, France. laurette@neurochem.u-strasbg.fr
Jokic
Natasa
N
Mbebi
Corinne
C
Boutillier
Stephanie
S
Loeffler
Jean-Philippe
JP
Boutillier
Anne-Laurence
AL
D000123:Acetyltransferases / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053178:Caspase 6; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000201:enzymology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051548:Histone Acetyltransferases; D006657:Histones / Q000302:isolation & purification / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D053178:Caspase 6; D020169:Caspases; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D051548:Histone Acetyltransferases; D006657:Histones; D011994:Recombinant Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C505516:Casp6 protein, mouse