Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway.
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.
Mesh Terms:
Blotting, Western, Cell Line, Cell Nucleus, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Gene Expression Regulation, Host Cell Factor C1, Humans, Immediate-Early Proteins, Immunoprecipitation, Mutagenesis, N-Acetylglucosaminyltransferases, Reverse Transcriptase Polymerase Chain Reaction, Simplexvirus
Blotting, Western, Cell Line, Cell Nucleus, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Gene Expression Regulation, Host Cell Factor C1, Humans, Immediate-Early Proteins, Immunoprecipitation, Mutagenesis, N-Acetylglucosaminyltransferases, Reverse Transcriptase Polymerase Chain Reaction, Simplexvirus
Proc. Natl. Acad. Sci. U.S.A.
Date: Feb. 15, 2011
PubMed ID: 21285374
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