title: Collapsin response mediator protein 3 deacetylates histone H4 to mediate nuclear condensation and neuronal death.
abstract: CRMP proteins play critical regulatory roles during semaphorin-mediated neurite outgrowth, neuronal differentiation and death. Albeit having a high degree of structure and sequence resemblance to that of liver dihydropyrimidinase, purified rodent brain CRMPs do not hydrolyze dihydropyrimidinase substrates. Here we found that mouse CRMP3 has robust histone H4 deacetylase activity. During excitotoxicity-induced mouse neuronal death, calpain-cleaved, N-terminally truncated CRMP3 undergoes nuclear translocation to cause nuclear condensation through deacetylation of histone H4. CRMP3-mediated deacetylation of H4 leads to de-repression of the E2F1 gene transcription and E2F1-dependent neuronal death. These studies revealed a novel mechanism of CRMP3 in neuronal death. Together with previous well established bodies of literature that inhibition of histone deacetylase activity provides neuroprotection, we envisage that inhibition of CRMP3 may represent a novel therapeutic approach towards excitotoxicity-induced neuronal death.
authors: Experimental NeuroTherapeutics Laboratory, NRC Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada. sheng.hou@nrc-cnrc.gc.ca
authors: Sheng T
authors: ST
authors: Hou
authors: Susan X
authors: SX
authors: Jiang
authors: Amy
authors: A
authors: Aylsworth
authors: Matthew
authors: M
authors: Cooke
authors: Lei
authors: L
authors: Zhou
mesh_terms: D000107:Acetylation; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure*; D050687:E2F1 Transcription Factor / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D014404:Tubulin
chemical_list: C405926:Dpysl4 protein, mouse; D050687:E2F1 Transcription Factor; D006657:Histones; D009419:Nerve Tissue Proteins; D014404:Tubulin; D018698:Glutamic Acid; D006655:Histone Deacetylases