YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA

Zhang, Zhaolong; Wang, Qiuhan; Zhao, Xiaolong; Shao, Liming; Liu, Shuai; Zheng, Xuan; Xie, Lingling; Zhang, Yan; Sun, Chengjian; Xu, Rui

doi:10.1038/s41419-020-03186-2

Cited by 95 publications

(73 citation statements)

References 42 publications

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“…Absorbance data were obtained using a 96-well plate reader (Molecular Devices, USA) at 490 nm. LDH release (%) was calculated by calculating the ratio of experimental LDH release to control LDH release according to the manufacturer’s instructions [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression

Cui

Zhang

Zhou

et al. 2021

J Neuroinflammation

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108

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Abstracts Background Many neurological diseases involve neuroinflammation, during which overproduction of cytokines by immune cells, especially microglia, can aggregate neuronal death. Ferroptosis is a recently discovered cell metabolism-related form of cell death and RSL3 is a well-known inducer of cell ferroptosis. Here, we aimed to investigate the effects of RSL3 in neuroinflammation and sensitivity of different type of microglia and macrophage to ferroptosis. Methods Here, we used quantitative RT-PCR analysis and ELISA analysis to analyze the production of proinflammatory cytokine production of microglia and macrophages after lipopolysaccharides (LPS) stimulation. We used CCK8, LDH, and flow cytometry analysis to evaluate the sensitivity of different microglia and macrophages to RSL3-induced ferroptosis. Western blot was used to test the activation of inflammatory signaling pathway and knockdown efficiency. SiRNA-mediated interference was conducted to knockdown GPX4 or Nrf2 in BV2 microglia. Intraperitoneal injection of LPS was performed to evaluate systemic inflammation and neuroinflammation severity in in vivo conditions. Results We found that ferroptosis inducer RSL3 inhibited lipopolysaccharides (LPS)-induced inflammation of microglia and peritoneal macrophages (PMs) in a cell ferroptosis-independent manner, whereas cell ferroptosis-conditioned medium significantly triggered inflammation of microglia and PMs. Different type of microglia and macrophages showed varied sensitivity to RSL3-induced ferroptosis. Mechanistically, RSL3 induced Nrf2 protein expression to inhibit RNA Polymerase II recruitment to transcription start site of proinflammatory cytokine genes to repress cytokine transcription, and protect cells from ferroptosis. Furthermore, simultaneously injection of RSL3 and Fer-1 ameliorated LPS-induced neuroinflammation in in vivo conditions. Conclusions These data revealed the proinflammatory role of ferroptosis in microglia and macrophages, identified RSL3 as a novel inhibitor of LPS-induced inflammation, and uncovered the molecular regulation of microglia and macrophage sensitivity to ferroptosis. Thus, targeting ferroptosis in diseases by using RSL3 should consider both the pro-ferroptosis effect and the anti-inflammation effect to achieve optimal outcome.

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Section: Methodsmentioning

confidence: 99%

Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression

Cui

Zhang

Zhou

et al. 2021

J Neuroinflammation

Self Cite

108

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“…A role for m 6 A readers as regulators of the brain response to stroke has also been proposed. YTHDC1 levels increased following ischemia in rats while YTHDF1, 2, and 3 levels were repressed ( Zhang et al, 2020 ). Elevated YTHDC1 levels may support post-ischemic neuronal survival via the modulation of the Akt/PTEN pathway ( Zhang et al, 2020 ).…”

Section: A In Brain Disordersmentioning

confidence: 99%

“…YTHDC1 levels increased following ischemia in rats while YTHDF1, 2, and 3 levels were repressed ( Zhang et al, 2020 ). Elevated YTHDC1 levels may support post-ischemic neuronal survival via the modulation of the Akt/PTEN pathway ( Zhang et al, 2020 ). YTHDF1 reduction may be a protective or adaptive mechanism by limiting post-stroke inflammation ( Zheng et al, 2020 ).…”

Section: A In Brain Disordersmentioning

confidence: 99%

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

Mathoux¹,

Henshall²,

Brennan³

2021

Front. Cell. Neurosci.

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RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.

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“…Thus hypothermia could activate PI3K/Akt signaling to protect neurons from I/R-induced pyroptosis ( Diao et al, 2020 ). Another study reported that the m 6 A reader YTHDC1 protects ischemic stroke through mediating PTEN mRNA degradation, which further promotes Akt phosphorylation and facilitates neuronal survival ( Zhang Z. et al, 2020 ). These two studies demonstrate that m 6 A modification could modulate PTEN expression to regulate PI3K/Akt signaling in I/R injury.…”

Section: A In Neurological Disorders and Injuriesmentioning

confidence: 99%

m6A Modification in Mammalian Nervous System Development, Functions, Disorders, and Injuries

2021

Front. Cell Dev. Biol.

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N6-methyladenosine (m6A) modification, as the most prevalent internal modification on mRNA, has been implicated in many biological processes through regulating mRNA metabolism. Given that m6A modification is highly enriched in the mammalian brain, this dynamic modification provides a crucial new layer of epitranscriptomic regulation of the nervous system. Here, in this review, we summarize the recent progress on studies of m6A modification in the mammalian nervous system ranging from neuronal development to basic and advanced brain functions. We also highlight the detailed underlying mechanisms in each process mediated by m6A writers, erasers, and readers. Besides, the involvement of dysregulated m6A modification in neurological disorders and injuries is discussed as well.

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YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA

Cited by 95 publications

References 42 publications

Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression

Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

m6A Modification in Mammalian Nervous System Development, Functions, Disorders, and Injuries

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