RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site

Li, Yiying; Zhang, Junting; Sun, Hanliang; Yu, Xuezhong; Chen, Yujie; Ma, Cui; Zheng, Xiaodong; Zhang, Lixin; Zhao, Xin; Jiang, Yuan; Wei, Xin; Wang, Shanshan; Hu, Jiye; Wang, Mingge; Zhu, Daling

doi:10.1016/j.omtn.2022.05.033

Cited by 10 publications

(8 citation statements)

References 56 publications

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“…The subsequent injections of wild-type and mutated LV-MKK3 significantly elevated the MKK3 level (Fig. 5D and E, F (8,18) = 93.04, both p < 0.001.). An immunofluorescence assay also showed wild-type and mutated LV-MKK3 expressed in hippocampus (Supplementary Fig.…”

Section: Mkk3 Mutation Disrupts the Interaction Between Mkk3 And Rage...mentioning

confidence: 80%

“…Fig. 6A and B show that the level of phosphorylated p65 in the hippocampus of db/db mice was higher than in db/m mice (F (5,18) = 64.54, p < 0.001) and that knockdown of MKK3 significantly reduced this increase (p < 0.001). Subsequent overexpression of wild-type MKK3 enhanced p65 phosphorylation (p = 0.002), but mutant MKK3 did not.…”

Section: Mutation Of Mkk3 Protects Against Hippocampal Neuroinflammat...mentioning

confidence: 92%

“…The overexpressed proteins were lysed in a homogenization buffer after overexpression. The GSTtagged vector pGEX-4T-1 was used to express RAGE and was translated and overexpressed in BL21 cells, followed by protein purification according to a GST protein interaction pull-down kit, following the manufacturer's instructions [18]. Briefly, 50 μL TBS containing the pulldown lysis buffer to pre-equilibrated agarose resin, and then 200 μL GST-tagged RAGE was co-incubated with the resin at 4°C for 6-8 h on a rotating platform, followed by washing five times.…”

Section: Gst Pull-downmentioning

confidence: 99%

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MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

2024

Aging dis

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The receptor for advanced glycation end products (RAGE) contributes to diabetes-associated cognitive dysfunction (DACD) through the interaction of its C-terminal AAs 2-5 with mitogen-activated protein kinase kinase 3 (MKK3). However, the associated MKK3 binding site is unknown. Here, db/db mice were used as a model for type 2 diabetes. GST pull-down assays and AutoDock Vina simulations were conducted to identify the key RAGE binding site in MKK3. This binding site was mutated to investigate its effects on DACD and to elucidate the underlying mechanisms. The interaction of MKK3 and RAGE, the levels of inflammatory factors, and the activation of microglia and astrocytes were tested. Synaptic morphology and plasticity in hippocampal neurons were assessed via electrophysiological recordings and Golgi staining. Behavioral tests were used to assess cognitive function. In this study, MKK3 bound directly to RAGE via its lysine 329 (K329), leading to the activation of the nuclear factor-κB (NF-κB) signaling pathway, which in turn triggered neuroinflammation and synaptic dysfunction, and ultimately contributed to DACD. MKK3 mutation at K329 reversed synaptic dysfunction and cognitive deficits by downregulating the NF-κB signaling pathway and inhibiting neuroinflammation. These results confirm that neuroinflammation and synaptic dysfunction in the hippocampus rely on the direct binding of MKK3 and RAGE. We conclude that MKK3 K329 binding to C-terminal RAGE (ct-RAGE) is a key mechanism by which neuroinflammation and synaptic dysfunction are induced in the hippocampus. This study presents a novel mechanism for DACD and proposes a novel therapeutic avenue for neuroprotection in DACD.

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Section: Mkk3 Mutation Disrupts the Interaction Between Mkk3 And Rage...mentioning

confidence: 80%

Section: Mutation Of Mkk3 Protects Against Hippocampal Neuroinflammat...mentioning

confidence: 92%

Section: Gst Pull-downmentioning

confidence: 99%

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MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

2024

Aging dis

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“…Along this line, studies by Li et al. pointed to lnc-Rps4l inhibiting hypoxia-induced PASMC pyroptosis through the encoded peptide RPS4XL ( 120 ).…”

Section: Epigenetic Regulation In Programmed Cell Death In Pahmentioning

confidence: 98%

Epigenetic regulation of programmed cell death in hypoxia-induced pulmonary arterial hypertension

Jiang,

Song,

Liu

et al. 2023

Front. Immunol.

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Pulmonary arterial hypertension (PAH) is a severe progressive disease that may cause early right ventricular failure and eventual cardiac failure. The pathogenesis of PAH involves endothelial dysfunction, aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs), and vascular fibrosis. Hypoxia has been shown to induce elevated secretion of vascular endothelial growth factor (VEGF), leading to the development of hypoxic PAH. However, the molecular mechanisms underlying hypoxic PAH remain incompletely understood. Programmed cell death (PCD) is a natural cell death and regulated by certain genes. Emerging evidence suggests that apoptotic resistance contributes to the development of PAH. Moreover, several novel types of PCD, such as autophagy, pyroptosis, and ferroptosis, have been reported to be involved in the development of PAH. Additionally, multiple diverse epigenetic mechanisms including RNA methylation, DNA methylation, histone modification, and the non-coding RNA molecule-mediated processes have been strongly linked to the development of PAH. These epigenetic modifications affect the expression of genes, which produce important changes in cellular biological processes, including PCD. Consequently, a better understanding of the PCD processes and epigenetic modification involved in PAH will provide novel, specific therapeutic strategies for diagnosis and treatment. In this review, we aim to discuss recent advances in epigenetic mechanisms and elucidate the role of epigenetic modifications in regulating PCD in hypoxia-induced PAH.

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“…Pyroptosis is involved in the development and progression of PH. HPASMC pyroptosis contributes to PH [9][10][11]. Inhibition of the NLRP3 pathway attenuates LPS-induced acute heart failure in monocrotaline-induced PH rats [12].…”

Section: Introductionmentioning

confidence: 99%

Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs

Wang

et al. 2022

Respir Res

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Background Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune processes. Disulfiram eliminates the formation of N-gasdermin D (GSDMD) plasma membrane pores to prevent pyroptosis. Pyroptosis is a form of lytic cell death characterized by inflammasome activation and proinflammatory cytokine release that acts in the development of PH. We sought to investigate whether disulfiram could alleviate hypoxia-induced PH by inhibiting pyroptosis. Methods To investigate whether disulfiram alleviates the progression of pulmonary hypertension, rodents were exposed to chronic hypoxia (10% oxygen, 4 weeks) to induce PH. The severity of PH was assessed by measuring right ventricular systolic pressure, mean pulmonary artery pressure, and the degree of right ventricular hypertrophy. Western blotting was used to measure proteins associated with the pyroptosis pathway, and ELISA was performed to measure the secretion of IL-18 and IL-1β, both of which are the primary methods for assessing pyroptosis. Results IL-18 and IL-1β concentrations were higher in patients with PH than in normal controls. Disulfiram suppressed the progression of PH in mice and rats through the alleviation of pulmonary arterial remodelling. Pyroptosis-related proteins and the inflammasome were activated in rodent models of PH. Disulfiram inhibited the processing of GSDMD into N-GSDMD and attenuated the secretion of IL-1β and IL18. In vivo experiments showed that disulfiram also inhibited lytic death in HPASMCs. Conclusions Disulfiram treatment reduces PH progression through suppressing vascular remodelling by inhibiting GSDMD cleavage and pyroptosis. It might become a novel therapeutic option for the treatment of PH.

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RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site

Cited by 10 publications

References 56 publications

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

Epigenetic regulation of programmed cell death in hypoxia-induced pulmonary arterial hypertension

Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs

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