Vitamin C Inhibits Ubiquitination of Glutamate Transporter 1 (GLT-1) in Astrocytes by Downregulating HECTD1

Zeng, Xiaokang; Dong, Xinhuai; Xiao, Qiang; Yao, Jie

doi:10.1021/acschemneuro.1c00845

Cited by 4 publications

(4 citation statements)

References 47 publications

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“…HECTD1 influences proliferation, apoptosis, autophagy, DNA damage repair, and mitochondrial function ( Beard et al 2016 ; Bennett et al 2020 ; Duhamel et al 2018 ; Liao et al 2023 ; Lu et al 2022 ; Segref et al 2014 ; Uemoto et al 2022 ; Vaughan et al 2022 ). HECTD1 is also involved in inflammation in astrocytes, microglia, and other cell types ( Li et al 2020 ; Liao et al 2023 ; Tang et al 2021 ; Zhang et al 2020 ) and can regulate synaptic function by regulating the expression of glutamate transporter 1 (GLT-1) in astrocytes ( Zeng et al 2022 ). Intriguingly, the Chinese NTD cohort utilized in this study was collected in a region where folate deficiency is well documented ( Liu et al 2016 ; Meng et al 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Rare HECTD1 Missense Variants in Human Neural Tube Defects

Oxman,

Li,

Wang

et al. 2024

Preprint

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Neural tube defects (NTDs) are severe malformations of the central nervous system that arise from failure of neural tube closure. HECTD1 is an E3 ubiquitin ligase required for cranial neural tube closure in mouse models. NTDs in the Hectd1 mutant mouse model are due to the failure of cranial mesenchyme morphogenesis during neural fold elevation. Our earlier research has linked increased secretion of extracellular heat shock protein 90 (eHSP90) to aberrant cranial mesenchyme morphogenesis in the Hectd1 model. Furthermore, overexpression of HECTD1 suppresses stress-induced eHSP90 secretion in cell lines. In this study, we report the identification of five rare HECTD1 missense sequence variants in NTD cases. The variants were found through targeted next-generation sequencing in a Chinese cohort of 352 NTD cases and 224 ethnically matched controls. We present data showing that HECTD1 is a highly conserved gene, extremely intolerant to loss-of-function mutations and missense changes. To evaluate the functional consequences of NTD-associated missense variants, functional assays in HEK293T cells were performed to examine protein expression and the ability of HECTD1 sequence variants to suppress eHSP90 secretion. One NTD-associated variant (A1084T) had significantly reduced expression in HEK293T cells. All five NTD-associated variants (p.M392V, p.T801I, p.I906V, p.A1084T, and p.P1835L) reduced regulation of eHSP90 secretion by HECTD1, while a putative benign variant (p.P2474L) did not. These findings are the first association of HECTD1 sequence variation with human disease and suggest that sequence variation in HECTD1 may play a role in the etiology of human NTDs.

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Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Rare HECTD1 Missense Variants in Human Neural Tube Defects

Oxman,

Li,

Wang

et al. 2024

Preprint

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“…In addition, we reported a new mechanism of VitC‐regulated protein ubiquitination. VitC was reported to lower glutamate transporter 1 (GLT‐1) ubiquitination in astrocytes by inhibiting the expression of the ubiquitin E3 ligase HECTD1 (Zeng et al , 2022). VitC can promote cancer cell death by inducing ubiquitination of the p34SEI‐1 oncoprotein mediated by the ubiquitin E3 ligase SIAH1 (Lee et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

Vitamin C promotes ACE2 degradation and protects against SARS‐CoV‐2 infection

et al. 2023

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ACE2 is a major receptor for cellular entry of SARS‐CoV‐2. Despite advances in targeting ACE2 to inhibit SARS‐CoV‐2 binding, strategies to flexibly and sufficiently reduce ACE2 levels for the prevention of SARS‐CoV‐2 infection have not been explored. Here, we reveal vitamin C (VitC) administration as a potent strategy to prevent SARS‐CoV‐2 infection. VitC reduces ACE2 protein levels in a dose‐dependent manner, while even a partial reduction in ACE2 levels can greatly inhibit SARS‐CoV‐2 infection. Further studies reveal that USP50 is a crucial regulator of ACE2 levels. VitC blocks the USP50‐ACE2 interaction, thus promoting K48‐linked polyubiquitination of ACE2 at Lys788 and subsequent degradation of ACE2 without affecting its transcriptional expression. Importantly, VitC administration reduces host ACE2 levels and greatly blocks SARS‐CoV‐2 infection in mice. This study reveals that ACE2 protein levels are down‐regulated by an essential nutrient, VitC, thereby enhancing protection against infection of SARS‐CoV‐2 and its variants.

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“…Ceftriaxone exerts the similar influence in epilepsy disease, which could upregulate GLT-1 expression by reducing glutamate in the hippocampus, mitigating the onset of seizures and the impairment of learning and memory in the chronic phase ( Ramandi et al, 2021 ). Vitamin C acts as a neuroprotective agent by promoting astrocyte GLT-1 expression, reducing glutamate aggregation, and attenuating excitatory damage in Parkinson’s disease (PD)( Zeng et al, 2022 ).…”

Section: Micrornas Regulate the Activities And Functions Of Reactive ...mentioning

confidence: 99%

MicroRNA-mediated regulation of reactive astrocytes in central nervous system diseases

Fan

Huang

Shao

et al. 2023

Front. Mol. Neurosci.

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Astrocytes (AST) are abundant glial cells in the human brain, accounting for approximately 20–50% percent of mammalian central nervous system (CNS) cells. They display essential functions necessary to sustain the physiological processes of the CNS, including maintaining neuronal structure, forming the blood–brain barrier, coordinating neuronal metabolism, maintaining the extracellular environment, regulating cerebral blood flow, stabilizing intercellular communication, participating in neurotransmitter synthesis, and defending against oxidative stress et al. During the pathological development of brain tumors, stroke, spinal cord injury (SCI), neurodegenerative diseases, and other neurological disorders, astrocytes undergo a series of highly heterogeneous changes, which are called reactive astrocytes, and mediate the corresponding pathophysiological process. However, the pathophysiological mechanisms of reactive astrocytes and their therapeutic relevance remain unclear. The microRNAs (miRNAs) are essential for cell differentiation, proliferation, and survival, which play a crucial role in the pathophysiological development of CNS diseases. In this review, we summarize the regulatory mechanism of miRNAs on reactive astrocytes in CNS diseases, which might provide a theoretical basis for the diagnosis and treatment of CNS diseases.

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Vitamin C Inhibits Ubiquitination of Glutamate Transporter 1 (GLT-1) in Astrocytes by Downregulating HECTD1

Cited by 4 publications

References 47 publications

Identification and Functional Analysis of Rare HECTD1 Missense Variants in Human Neural Tube Defects

Identification and Functional Analysis of Rare HECTD1 Missense Variants in Human Neural Tube Defects

Vitamin C promotes ACE2 degradation and protects against SARS‐CoV‐2 infection

MicroRNA-mediated regulation of reactive astrocytes in central nervous system diseases

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