Augmented O-GlcNAcylation attenuates intermittent hypoxia-induced cardiac remodeling through the suppression of NFAT and NF-κB activities in mice

Nakagawa, Takatoshi; Furukawa, Yoichi; Hayashi, Toshio; Nomura, Atsuo; Yokoe, Shunichi; Moriwaki, Kazumasa; Kato, Ryuichi; Ijiri, Yoshio; Yamaguchi, Takehiro; Izumi, Yasukatsu; Yoshiyama, Minoru; Asahi, Michio

doi:10.1038/s41440-019-0311-x

Cited by 15 publications

(14 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another example is store-operated Ca 2+ entry that is negatively controlled by STIM1 O-GlcNAcylation (Zhu-Mauldin et al, 2012), and could play roles in multiple mechanical and receptor-coupled signaling. O-GlcNAcylation of NFKB p65 and GSK-3β has been previously linked to reduced NFAT signaling with intermittent hypoxia (Nakagawa et al, 2019), but the sites of modification and constitutive status are not reported yet. While TRPC6 phophorylation bi-directionally modulates TRPC6 function and protein interaction, to our knowledge, this has not been found obligatory for basal functionality.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Inhibition of Transient Receptor Potential Canonical Type 6 (TRPC6) by O-GlcNAcylation at Threonine-221

Kass

Mishra

et al. 2022

Preprint

View full text Add to dashboard Cite

Transient receptor potential canonical type 6 (TRPC6) is a non-voltage gated cation channel that principally conducts calcium to regulate signaling in cardiac, vascular, neuronal and other cells. Abnormally increased TRPC6 expression/conductance and genetic gain of function mutations contribute to fibrosis, hypertrophy, proteinuria, and edema, notably linked to its stimulation of nuclear factor of activated T-cells (NFAT) signaling. Hyperglycemia (HG) also activates TRPC6/NFAT as a cause of diabetic renal disease. While prior work linked HG-TRPC6 activation to oxidant stress, the role of another major HG modification - O-GlcNAcylation, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated, TRPC6 and O-GlcNAc transferase proteins interact, this modification potently suppresses basal channel conductance and NFAT activity, and it is unaltered by HG. Proteomics identifies O-GlcNAcylation at Ser14, Thr70, and Thr221 in the N-terminus ankyrin-4 (AR4) and neighboring linker (LH1) domains of TRPC6. Of these, T221 is most impactful as a T221A mutation increases basal NFAT activity 11-fold, TRPC6 conductance 75-80% vs wild-type, and when expressed in cardiomyocytes amplifies NFAT-pro-hypertrophic gene expression. T221 is highly conserved and mutating homologs in TRPC3 and TRPC7 also markedly elevates basal NFAT activity. Molecular models predict electrostatic interactions between T221 O-GlcNAc and Ser199, Glu200, and Glu246, and we find similarly elevated NFAT activity from alanine substitutions at these coordinating sites as well. Thus, O-GlcNAcylation at T221 and its interaction with coordinating residues in AR4-LH1 is required for basal TRPC6 channel conductance and regulation of NFAT.

show abstract

Section: Discussionmentioning

confidence: 99%

Constitutive Inhibition of Transient Receptor Potential Canonical Type 6 (TRPC6) by O-GlcNAcylation at Threonine-221

Kass

Mishra

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The effect of NF‐κB activation on the upregulation of IL‐6 expression under cold stress or various adverse conditions has been reported previously (Hu et al, 2020; C. W. Liu et al, 2018; McFarland et al, 2013; M. Zhang et al, 2018; S. Zhang et al, 2019). OGT‐mediated O ‐GlcNAcylation promotes NF‐κB activation and modulates NF‐κB signaling (Nakagawa et al, 2019; Y. R. Yang et al, 2015; D. Zhang et al, 2015). The changes in p65 expression and activity observed in both our in vivo and in vitro studies are consistent with these previous reports.…”

Section: Discussionmentioning

confidence: 99%

“…However, the precise regulatory mechanisms underlying this response remain unclear (Y. Liu, Xu, et al, 2021; Yao et al, 2018). Interestingly, several studies have suggested that OGT‐mediated O ‐GlcNAcylation promotes activation of the NF‐κB family member p65 to regulate the expression of downstream proteins (Nakagawa et al, 2019; Ramakrishnan et al, 2013; D. Zhang et al, 2015). As the regulation of IL‐6 by p65 has been widely reported (Hu et al, 2020; Liang et al, 2017; M. Zhang et al, 2018), we hypothesized that OGT plays a cytoprotective role by enhancing glucose metabolism and mediating OGT‐dependent O ‐GlcNAcylation of p65 to up‐regulate IL‐6 in the skeletal muscle of mice during cold exposure.…”

Section: Introductionmentioning

confidence: 99%

OGT upregulates myogenic IL‐6 by mediating O‐GlcNAcylation of p65 in mouse skeletal muscle under cold exposure

Liu

Yang

et al. 2021

Journal Cellular Physiology

View full text Add to dashboard Cite

Cold exposure is an unavoidable and severe challenge for people and animals residing in cold regions of the world, and may lead to hypothermia, drastic changes in systemic metabolism, and inhibition of protein synthesis. O‐linked‐N‐acetylglucoseaminylation (O‐GlcNAcylation) directly regulates the activity and function of target proteins involved in multiple biological processes by acting as a stress receptor and nutrient sensor. Therefore, our study aimed to examine whether O‐GlcNAcylation affected myogenic IL‐6 expression, regulation of energy metabolism, and promotion of survival in mouse skeletal muscle under acute cold exposure conditions. Total protein was extracted from C2C12 cells that had been cultured at 32°C for 3, 6, 9, and 12 h. Western blot analysis showed that mild hypothermia enhanced O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) expression. Furthermore, global OGT‐dependent glycosylation and interleukin‐6 (IL‐6) levels peaked 3 h after induction of mild hypothermia. Enhanced activation of the NF‐κB pathway was also observed in response to mild hypothermia. Alloxan and Thiamet G were used to reduce and increase global OGT glycosylation levels in C2C12 cells, respectively. Increased O‐GlcNAcylation was associated with significant upregulation of IL‐6 expression, as well as enhanced activity and nuclear translocation of p65, while decreased O‐GlcNAcylation had the opposite effect. In addition, increased O‐GlcNAcylation was associated with significantly increased glucose metabolism, and OGT‐mediated O‐GlcNAcylation of p65. We generated skeletal muscle‐specific OGT knockout mice and exposed them to cold at 4°C for 3 h per day for 1 week. OGT deficiency attenuated the O‐GlcNAcylation, activity, and nuclear translocation of p65, resulting in downregulation of IL‐6 in mouse skeletal muscle of mice exposed to cold conditions. Taken together, our data suggested that O‐GlcNAcylation of p65 enhanced p65 activity and nuclear translocation leading to the upregulation of IL‐6, which maintained energy homeostasis and promotes cell survival in mouse skeletal muscle during cold exposure.

show abstract

“…Yet, in the absence of O-GlcNAc, IL-2 production and T cell proliferation were compromised ( 126 ). Controversially, augmented O-GlcNAc levels in heart tissue and rat cardiomyocyte-derived cell line suppressed NFAT and NF-κB activity through GSK-3β protein O-GlcNAcylation ( 127 ). It seems that O-GlcNAcylation antagonizes NFAT effects, since GSK-3β is known to negatively regulate NFAT activity ( 128 ).…”

Section: Possible Mechanisms Whereby the Crosstalk Between O-glcnacyl...mentioning

confidence: 99%

O-Linked β-N-Acetylglucosamine Modification: Linking Hypertension and the Immune System

et al. 2022

View full text Add to dashboard Cite

The O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of proteins dynamically regulates protein function, localization, stability, and interactions. This post-translational modification is intimately linked to cardiovascular disease, including hypertension. An increasing number of studies suggest that components of innate and adaptive immunity, active players in the pathophysiology of hypertension, are targets for O-GlcNAcylation. In this review, we highlight the potential roles of O-GlcNAcylation in the immune system and discuss how those immune targets of O-GlcNAcylation may contribute to arterial hypertension.

show abstract

Augmented O-GlcNAcylation attenuates intermittent hypoxia-induced cardiac remodeling through the suppression of NFAT and NF-κB activities in mice

Cited by 15 publications

References 28 publications

Constitutive Inhibition of Transient Receptor Potential Canonical Type 6 (TRPC6) by O-GlcNAcylation at Threonine-221

Constitutive Inhibition of Transient Receptor Potential Canonical Type 6 (TRPC6) by O-GlcNAcylation at Threonine-221

OGT upregulates myogenic IL‐6 by mediating O‐GlcNAcylation of p65 in mouse skeletal muscle under cold exposure

O-Linked β-N-Acetylglucosamine Modification: Linking Hypertension and the Immune System

Contact Info

Product

Resources

About