title: Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation.
abstract: The transcription factor cyclic AMP-response element binding protein (CREB) is a key regulator of many neuronal processes, including brain development, circadian rhythm and long-term memory. Studies of CREB have focused on its phosphorylation, although the diversity of CREB functions in the brain suggests additional forms of regulation. Here we expand on a chemoenzymatic strategy for quantifying glycosylation stoichiometries to characterize the functional roles of CREB glycosylation in neurons. We show that CREB is dynamically modified with an O-linked β-N-acetyl-D-glucosamine sugar in response to neuronal activity and that glycosylation represses CREB-dependent transcription by impairing its association with CREB-regulated transcription coactivator (CRTC; also known as transducer of regulated CREB activity). Blocking glycosylation of CREB alters cellular function and behavioral plasticity, enhancing both axonal and dendritic growth and long-term memory consolidation. Our findings demonstrate a new role for O-glycosylation in memory formation and provide a mechanistic understanding of how glycosylation contributes to critical neuronal functions. Moreover, we identify a previously unknown mechanism for the regulation of activity-dependent gene expression, neural development and memory.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Rexach
authors.forename: Peter M
authors.initials: PM
authors.lastname: Clark
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Mason
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsieh-Wilson
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006031:Glycosylation; D057567:Memory, Long-Term; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D000117:Acetylglucosamine