title: Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway.
abstract: Host Cell Factor 1 (HCF-1) plays critical roles in regulating gene expression in a plethora of physiological processes. HCF-1 is first synthesized as a precursor, and subsequently specifically proteolytically cleaved within a large middle region termed the proteolytic processing domain (PPD). Although the underlying mechanism remains enigmatic, proteolysis of HCF-1 regulates its transcriptional activity and is important for cell cycle progression. Here we report that HCF-1 proteolysis is a regulated process. We demonstrate that a large proportion of the signaling enzyme O-linked-N-acetylglucosaminyl transferase (OGT) is complexed with HCF-1 and this interaction is essential for HCF-1 cleavage. Moreover, HCF-1 is, in turn, required for stabilizing OGT in the nucleus. We provide evidence indicating that OGT regulates HCF-1 cleavage via interaction with and O-GlcNAcylation of the HCF-1 PPD. In contrast, although OGT also interacts with the basic domain in the HCF-1 amino-terminal subunit, neither the interaction nor the O-GlcNAcylation of this region are required for proteolysis. Moreover, we show that OGT-mediated modulation of HCF-1 impacts the expression of the herpes simplex virus immediate-early genes, targets of HCF-1 during the initiation of viral infection. Together the data indicate that O-GlcNAcylation of HCF-1 is a signal for its proteolytic processing and reveal a unique crosstalk between these posttranslational modifications. Additionally, interactions of OGT with multiple HCF-1 domains may indicate that OGT has several functions in association with HCF-1.
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4.
authors.forename: Salima
authors.initials: S
authors.lastname: Daou
authors.forename: Nazar
authors.initials: N
authors.lastname: Mashtalir
authors.forename: Ian
authors.initials: I
authors.lastname: Hammond-Martel
authors.forename: Helen
authors.initials: H
authors.lastname: Pak
authors.forename: Helen
authors.initials: H
authors.lastname: Yu
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Vogel
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kristie
authors.forename: El Bachir
authors.initials: el B
authors.lastname: Affar
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D051863:Host Cell Factor C1 / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D016296:Mutagenesis; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000378:metabolism
chemical_list: C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D017874:Immediate-Early Proteins; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase