O-GlcNAcylation of SKN-1 modulates the lifespan and oxidative stress resistance in Caenorhabditis elegans

Li, Hongyuan; Liu, Xin; Wang, Dan; Su, Lili; Zhao, Tingting; Li, Zhongwei; Lin, Cong; Huang, Baiqu; Lü, Jun; Li, Xiaoxue

doi:10.1038/srep43601

Cited by 40 publications

(47 citation statements)

References 41 publications

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“…Therefore, we speculate that TCF11 somehow has attained an opposite OGT mediated regulatory mechanism as it began to be expressed later in phylogeny. In this regard, it is interesting that SKN1, an Nrf1 ortholog present in C. elegans, was recently shown to be positively regulated by an OGT interaction similar to that with Nrf1a shown in our investigation [72]. As of now however, there are no studies elucidating the functional difference between TCF11 and Nrf1a.…”

Section: Discussionmentioning

confidence: 62%

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

Han

Valdez

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C TThe Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O-GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a.

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Section: Discussionmentioning

confidence: 62%

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

Han

Valdez

et al. 2017

Free Radical Biology and Medicine

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“…C. elegans is the primary genetic model system for studies of ogt-1 because it is the only organism in which loss of ogt-1 is viable (25,26). This has allowed many previous studies to parse the roles of ogt-1 in lifespan, metabolism, innate immunity, behavior, neuron function, stress responses, cell fate, and autophagy (18,22,25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Importantly, most of these studies utilized global ogt-1 knockdown, which eliminates both O-GlcNAcylation-dependent and -independent functions of ogt-1.…”

Section: Discussionmentioning

confidence: 99%

“…Previous data has shown that it plays both a transcriptional and posttranscriptional role in stress response gene expression. For example, OGT-1 O-GlcNAcylates the oxidative stress responsive transcription factor SKN-1 to facilitate upregulation of antioxidant gene transcription (32). On the other hand, OGT regulates UPR ER and HSR gene expression post-transcriptionally by O-GlcNAcylating translation initiation factors to selectively facilitate translation of stress induced mRNAs (43,44).…”

Section: Knockout Of Ogt In Mammalian Cells Leads To a Rapid Loss In mentioning

confidence: 99%

TheO-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress

Urso

Comly

Hanover

et al. 2020

Preprint

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The conserved O-GlcNAc transferase OGT O-GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology: the hypertonic stress response. Through a forward genetic screen in Caenorhabditis elegans, we discovered OGT is acutely required for osmoprotective protein expression and adaptation to hypertonic stress. Gene expression analysis shows that ogt-1 functions through a post-transcriptional mechanism. Human OGT partially rescues the C. elegans phenotypes, suggesting that the osmoregulatory functions of OGT are ancient. Intriguingly, mutations that ablate O-GlcNAcylation activity in either human or C. elegansOGT rescue the hypertonic stress response phenotype. Our findings are among the first to demonstrate a specific physiological role for OGT at the organismal level and demonstrate that OGT engages in important molecular functions outside of its well described roles in post-translational O-GlcNAcylation of intracellular proteins. Author SummaryThe ability to sense and adapt to changes in the environment is an essential feature of cellular life. Changes in environmental salt and water concentrations can rapidly cause cell volume swelling or shrinkage and, if left unchecked, will lead to cell and organismal death. All organisms have developed similar physiological strategies for maintaining cell volume. However, the molecular mechanisms that control these physiological outputs are not well understood in animals. Using unbiased genetic screening in C. elegans, we discovered that a highly conserved enzyme called O-GlcNAc transferase (OGT) is essential for regulating physiological responses to increased environmental solute levels. A human form of OGT can functionally substitute for worm OGT, showing that this role is conserved across evolution. Surprisingly, the only known enzymatic activity of OGT was not required for this role, suggesting this enzyme has important undescribed molecular functions. Our studies reveal a new animal-specific role for OGT in the response to osmotic stress and show that C. elegans is an important model for defining the conserved molecular mechanisms that respond to alterations in cell volume.

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“…Interestingly, recent studies have identified cross‐talk between O‐GlcNAcylation and the NRF2 pathway in different species and experimental models. For example, SKN‐1, the NRF ortholog in Caenorhabditis elegans , is O‐GlcNAcylated in response to oxidative stress (Li et al , ). Although we did not detect evidence of NRF2 O‐GlcNAcylation under homeostasis conditions (Fig A), human NRF proteins may be glycosylated in response to oxidative stress or other triggers.…”

Section: Discussionmentioning

confidence: 99%

Glycosylation of KEAP1 links nutrient sensing to redox stress signaling

et al. 2017

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O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient-sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts.

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O-GlcNAcylation of SKN-1 modulates the lifespan and oxidative stress resistance in Caenorhabditis elegans

Cited by 40 publications

References 41 publications

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

TheO-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress

Glycosylation of KEAP1 links nutrient sensing to redox stress signaling

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