HCF-1 Is Cleaved in the Active Site of O-GlcNAc Transferase

Lazarus, Michael B.; Jiang, Jiaoyang; Kapuria, Vaibhav; Bhuiyan, Tanja; Janetzko, John; Zandberg, Wesley F.; Vocadlo, David J.; Herr, Winship; Walker, Suzanne

doi:10.1126/science.1243990

Cited by 172 publications

(280 citation statements)

References 37 publications

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“…2). Decreased proliferation may also stem from inhibiting the protease activity of OGT, which is responsible for cleaving HCFC1, a regulator of the cell cycle (79,80). Through the use of stable isotope labeling, we detected a greater abundance of O-GlcNAc-modified peptides from UBAP2L and NUP214 after T cell activation.…”

Section: Discussionmentioning

confidence: 98%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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T cell activation in response to Ag is largely regulated by protein posttranslational modifications. Although phosphorylation has been extensively characterized in T cells, much less is known about the glycosylation of serine/threonine residues by O-linked N-acetylglucosamine (O-GlcNAc). Given that O-GlcNAc appears to regulate cell signaling pathways and protein activity similarly to phosphorylation, we performed a comprehensive analysis of O-GlcNAc during T cell activation to address the functional importance of this modification and to identify the modified proteins. Activation of T cells through the TCR resulted in a global elevation of O-GlcNAc levels and in the absence of O-GlcNAc, IL-2 production and proliferation were compromised. T cell activation also led to changes in the relative expression of O-GlcNAc transferase (OGT) isoforms and accumulation of OGT at the immunological synapse of murine T cells. Using a glycoproteomics approach, we identified >200 O-GlcNAc proteins in human T cells. Many of the identified proteins had a functional relationship to RNA metabolism, and consistent with a connection between O-GlcNAc and RNA, inhibition of OGT impaired nascent RNA synthesis upon T cell activation. Overall, our studies provide a global analysis of O-GlcNAc dynamics during T cell activation and the first characterization, to our knowledge, of the O-GlcNAc glycoproteome in human T cells.

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Section: Discussionmentioning

confidence: 98%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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“…The HDACs remove the acetyl residue laid down by the numerous histone acetyltransferases, which use acetyl-CoA as a precursor (1, 5). The OGT-mSin3A complex is also found in association with HCF-1, a protein that is cleaved by OGT in a process linked to mitotic cell cycle progression (45,(62)(63)(64). OGT is also a central hub in the Oct4 network and associates with other factors maintaining stem cell pluripotency (26).…”

Section: O-glcnac and Epigenetic Regulation Of Transcription By The Hmentioning

confidence: 99%

O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

126

116

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O-GlcNAcylation is an abundant nutrient-driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic flux, O-GlcNAc functions as a homeostatic regulator. The enzymes of O-GlcNAc cycling, OGT and O-GlcNAcase, act in mitochondria, the cytoplasm, and the nucleus in association with epigenetic "writers" and "erasers" of the histone code. Both O-GlcNAc and O-phosphate modify repeats within the RNA polymerase II C-terminal domain (CTD). By communicating with the histone and CTD codes, O-GlcNAc cycling provides a link between cellular metabolic status and the epigenetic machinery. Thus, O-GlcNAcylation is poised to influence transgenerational epigenetic inheritance.Intermediary metabolism, the process by which nutrients are converted into cellular biomass, is an interwoven network of biochemical reactions allowing reproduction, development, and response to the environment. The intermediary metabolic network is highly conserved and includes every cellular process ranging from DNA replication to transcription and translation to enzyme regulation. Epigenetics, the study of how genes may alter phenotypes beyond their ability to genetically encode information, is ultimately linked to intermediary metabolism (1). Many enzymes that participate in epigenetic gene regulation depend upon co-substrates produced by cellular metabolism, thus providing a potential link between metabolism and gene regulation (2). Mitochondria, key players in these metabolic inter-conversions, exhibit a pattern of cytoplasmic inheritance distinct from Mendelian inheritance of genes encoded in the nucleus (3). O-GlcNAcylation is a key integrator of cellular nutritional status and occurs in the nucleus, cytoplasm, and mitochondrion. O-GlcNAc transferase (OGT) 3 utilizes UDP-GlcNAc to catalyze the addition of O-GlcNAc to target proteins. UDP-GlcNAc is the end product of the hexosamine biosynthetic pathway (HSP), a series of enzymatic reactions requiring key metabolites, including glucose, glutamine, ATP, and acetyl-CoA (4). The nutrient-derived precursors render the synthesis of UDP-GlcNAc and subsequent O-GlcNAc addition by OGT nutrient-responsive. The O-GlcNAcase (OGA; MGEA5) removes the O-GlcNAc modification, and evidence suggests that its transcription and activity is highly regulated. Both enzymes of O-GlcNAc cycling contain domains that allow them to bind to epigenetic modifiers (5, 6). As illustrated in Fig. 1, UDP-GlcNAc is central both to the formation of O-GlcNAc but also to the synthesis of membrane and secretory glycoproteins that perform essential roles in extracellular signaling. The intracellular O-GlcNAc modification plays a role in signaling, leading to growth and apoptosis (7-9), metabolism (10, 11), and the cell cycle (12)(13)(14). In addition, O-GlcNAc has been implicated in translation (15), circadian rhythm (16), the establishment of molecular memory in neurons (17), and calmodulinkinase signaling (16). The focus of this review is the role of O-GlcNAc in transcripti...

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“…The N-terminal subunit HCF-1 N promotes progression through G1 whereas the C-terminal subunit HCF-1 C regulates mitosis and cytokinesis [84][85][86]. Additionally to previous findings suggesting the interaction of OGT with HCF-1 and its glycosylation [87,88] recent studies have shown that OGT is required for HCF-1 proteolytic processing [78,89,90]. Daou et al demonstrated that a large proportion of the OGT in cells are in complex with HCF-1 and that this interaction is essential for HCF-1 cleavage [89].…”

Section: Ogt and Hcf-1mentioning

confidence: 96%

“…Capotosti et al revealed that OGT not only glycosylated HCF-1 but also directly cleaved HCF-1 PRO domain [78]. Finally, Lazarus et al fully elucidated the cleavage process [90]. They reported that the tetratricopeptide-repeat domain of OGT bound the C-terminal portion of a HCF-1 proteolytic repeat such that the cleavage region lay in the glycosylotransferase active site above uridine diphosphate-GlcNAc.…”

Section: Ogt and Hcf-1mentioning

confidence: 99%

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The potential role of O-GlcNAc modification in cancer epigenetics

Forma

Jóźwiak

Bryś

et al. 2014

Cellular and Molecular Biology Letters

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There is no doubt that cancer is not only a genetic disease but that it can also occur due to epigenetic abnormalities. Diet and environmental factors can alter the scope of epigenetic regulation. The results of recent studies suggest that O-GlcNAcylation, which involves the addition of N-acetylglucosamine on the serine or threonine residues of proteins, may play a key role in the regulation of the epigenome in response to the metabolic status of the cell. Two enzymes are responsible for cyclic O-GlcNAcylation: O-GlcNAc transferase (OGT), which catalyzes the addition of the GlcNAc moiety to target proteins; and O-GlcNAcase (OGA), which removes the sugar moiety from proteins. Aberrant expression of O-GlcNAc cycling enzymes, especially OGT, has been found in all studied human cancers. OGT can link the cellular metabolic state and the epigenetic status of cancer cells by interacting with and modifying many epigenetic factors, such as HCF-1, TET, mSin3A, HDAC, and BAP1. A growing body of evidence from animal model systems also suggests an important role for OGT in polycomb-dependent repression of genes activity. Moreover, O-GlcNAcylation may be a part of the histone code: O-GlcNAc residues are found on all core histones.

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HCF-1 Is Cleaved in the Active Site of O-GlcNAc Transferase

Cited by 172 publications

References 37 publications

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

O-GlcNAc and the Epigenetic Regulation of Gene Expression

The potential role of O-GlcNAc modification in cancer epigenetics

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