A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome

Keembiyehetty, Chithra N.; Krześlak, Anna; Love, Dona C.; Hanover, John A.

doi:10.1242/jcs.083287

Cited by 82 publications

(87 citation statements)

References 41 publications

(61 reference statements)

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“…Selective knockdown of OGA-S results in global proteasome inhibition and increased levels of perilipin-2 and -3. These findings suggest that proteasomal modulation links O-GlcNAc signaling to lipid droplet maturation (71).…”

Section: O-glcnacylation Regulates Protein Ubiquitination Via Unknownmentioning

confidence: 77%

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Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Ruan

Nie

Yang

2013

Molecular & Cellular Proteomics

148

119

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The post-translational modification of intracellular proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates essential cellular processes such as signal transduction, transcription, translation, and protein degradation. Misfolded, damaged, and unwanted proteins are tagged with a chain of ubiquitin moieties for degradation by the proteasome, which is critical for cellular homeostasis. In this review, we summarize the current knowledge of the interplay between O-GlcNAcylation and ubiquitination in the control of protein degradation. Understanding the mechanisms of action of O-GlcNAcylation in the ubiquitin-proteosome system shall facilitate the development of therapeutics for human diseases such as cancer, metabolic syndrome, and neurodegenerative diseases. Molecular & Cellular

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Section: O-glcnacylation Regulates Protein Ubiquitination Via Unknownmentioning

confidence: 77%

“…The short form of O-GlcNAcase (OGA-S), which lacks the histone acetyltransferase domain, accumulates on the surface of lipid droplets (71). Selective knockdown of OGA-S results in global proteasome inhibition and increased levels of perilipin-2 and -3.…”

Section: O-glcnacylation Regulates Protein Ubiquitination Via Unknownmentioning

confidence: 99%

Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Ruan

Nie

Yang

2013

Molecular & Cellular Proteomics

148

119

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“…HAS2 is known to be mono-and polyubiquitinated, and although monoubiquitination seems to be involved in enzyme dimerization, polyubiquitination does not seem directly related to proteasomal degradation (13). Recently, it was described that the short OGA isoform promotes the proteasomal degradation of surface lipid droplet proteins (54,55) and therefore could have a role in the regulation of HAS2 degradation. Moreover, very recent literature describes the presence of an OGT in the ER (EOGT) conserved in Drosophila and mice (56,57), which could regulate the HAS2 folding process or its escape from the ER.…”

Section: Discussionmentioning

confidence: 99%

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Vigetti

Deleonibus

Moretto

et al. 2012

Journal of Biological Chemistry

131

114

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Background: UDP-GlcNAc is a precursor of glycoconjugates, including hyaluronan, and induces protein glycosylation to form O-linked GlcNAc (O-GlcNAcylation). Results: UDP-GlcNAc induces hyaluronan synthesis through O-GlcNAcylation of hyaluronan synthase 2, which stabilizes the enzyme and prevents its proteasomal degradation. Conclusion: O-GlcNAcylation of hyaluronan synthase 2 can control synthesis of extracellular matrices with hyaluronan. Significance: UDP-GlcNAc could control cell microenvironments that are altered in many pathologies, including vascular diseases and cancer.

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“…The other major O-GlcNAcase isoform has a 14-amino extension that serves to target it to lipid droplets. This O-GlcNAcase isoform is involved in the remodeling of lipid droplet surface proteins by local activation of proteasomes on the lipid droplet surface (38,42). This study suggested a nexus between the regulation of lipid storage and hexosamine signaling through O-GlcNAc cycling (42).…”

mentioning

confidence: 89%

O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

Self Cite

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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A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome

Cited by 82 publications

References 41 publications

Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

O-GlcNAc and the Epigenetic Regulation of Gene Expression

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