Functional suppression of Ripk1 blocks the NF-κB signaling pathway and induces neuron autophagy after traumatic brain injury

Li, Jun; Zhu, Zhengkun; Wang, Leibo; Du, Jixiang; Zhang, Biao; Feng, Xuequan; Zhang, Guobin

doi:10.1007/s11010-020-03789-5

Cited by 24 publications

(10 citation statements)

References 26 publications

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“…It has been reported that TRIM25, BCL10 and RIPK1 positively regulate the activation of NF-κB [29][30][31], whereas NFKBIA suppresses the activation of NF-κB [32]. In this study, we revealed that NFIL3 negatively regulates the expression of NFKBIA but positively regulates the expression of BCL10 and RIPK1, consistent with the roles of NFIL3 in regulating NF-κB activity.…”

Section: Discussionsupporting

confidence: 87%

Elevated Expression of The Rhythm Gene NFIL3 Promotes The Progression of TNBC By Activating NF-κB Signaling Through Suppression of NFKBIA Transcription

Yang

Zhang

et al. 2021

Preprint

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Background: Epidemiological studies have confirmed that abnormal circadian rhythms are associated with tumorigenesis in breast cancer. However, few studies have investigated the pathological roles of rhythm genes in breast cancer progression. Methods: The expressions of NFIL3 and NFKBIA were measured by Western blot, qRT–PCR and IHC analysis. The proliferation and metastasis of two TNBC cell lines were analyzed by cell counting assays, clone formation assays, subcutaneous tumor formation assay, wound healing assays, transwell assays and the mouse tail vein injection model.Results: We evaluated the aberrant expression of 32 rhythm genes in breast cancer and identified that nuclear factor interleukin 3 regulated (NFIL3) expression is significantly altered in triple-negative breast cancer (TNBC). We found that NFIL3 inhibits its own transcription, and thus, downregulated NFIL3 mRNA indicates high expression of NFIL3 protein in breast cancer. Functional studies demonstrated that NFIL3 promotes the proliferation and metastasis of TNBC cells in vitro and in vivo. Higher expression of NFIL3 is associated with poor prognosis of patients with TNBC. Gene enrichment assays revealed that NFIL3 primarily regulates cancer-associated inflammation. Correlation analysis showed that expression of NFIL3 is associated with infiltration level of various immune cells in breast cancer. We further demonstrated that NFIL3 enhances the activity of NF-κB signaling. Mechanistically, we revealed that NFIL3 directly suppresses the transcription of NFKBIA, which blocks the activation of NF-κB and inhibits the progression of TNBC cells in vitro and in vivo. Moreover, we showed that enhancing NF-κB activity by repressing NFKBIA largely mimics the oncogenic effect of NFIL3 in TNBC, and anti-inflammatory strategies targeting NF-κB activity block the oncogenic roles of NFIL3 in TNBC. Conclusion:NFIL3 promotes the progression of TNBC by suppressing NFKBIA and then enhancing NF-κB signaling-mediated cancer-associated inflammation. This study may provide a new target for TNBC prevention and therapy.

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Section: Discussionsupporting

confidence: 87%

Elevated Expression of The Rhythm Gene NFIL3 Promotes The Progression of TNBC By Activating NF-κB Signaling Through Suppression of NFKBIA Transcription

Yang

Zhang

et al. 2021

Preprint

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“…We previously described a role for RIPK signaling in inflammatory transcriptional activation in neurons that was independent of necroptotic cell death [ 34 ]. Moreover, RIPK signaling is a known activator of the NF-κB pathway [ 48 – 51 ]. We thus questioned whether RIPK signaling was required for PFF-mediated astrocyte activation.…”

Section: Resultsmentioning

confidence: 99%

Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

et al. 2021

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of the disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

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“…RIPK1 is the first discovered molecule in the necroptosis pathway [16], it contributes to neuronal and astrocytic cell death in ischemic stroke via activating autophagic-lysosomal pathway [17]. Functional suppression of RIPK1 blocks the NF-κB signaling pathway and induces neuron autophagy after traumatic brain injury [18]. On the other hand, autophagy-initiating kinase the Ser/Thr kinase unc-51 like kinase 1 controls RIPK1-mediated cell death [19].…”

Section: Discussionmentioning

confidence: 99%

RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts

et al. 2022

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Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are critical regulators of programmed necrosis or necroptosis. However, the role of the RIPK1/RIPK3 signaling pathway in myocardial fibrosis and related diabetic cardiomyopathy is still unclear. We hypothesized that RIPK1/RIPK3 activation mediated myocardial fibrosis by impairing the autophagic flux. To this end, we established in vitro and in vivo models of type 2 diabetes mellitus with high glucose fat (HGF) medium and diet respectively. HGF induced myocardial fibrosis, and impaired cardiac diastolic and systolic function by activating the RIPK1/RIPK3 pathway, which increased the expression of autophagic related proteins such as LC3-II, P62 and active-cathepsin D. Inhibition of RIPK1 or RIPK3 alleviated HGF-induced death and fibrosis of cardiac fibroblasts by restoring the impaired autophagic flux. The autophagy blocker neutralized the effects of the RIPK1 inhibitor necrostatin-1 (Nec-1) and RIPK3 inhibitor GSK872 (GSK). RIPK1/RIPK3 inhibition respectively decreased the levels of RIPK3/p-RIPK3 and RIPK1/p-RIPK1. P62 forms a complex with RIPK1-RIPK3 and promotes the binding of RIPK1 and RIPK3, silencing of RIPK1 decreased the association of RIPK1 with P62 and the binding of P62 to LC3. Furthermore, inhibition of both kinases in combination with a low dose of Nec-1 and GSK in the HGF-treated fibroblasts significantly decreased cell death and fibrosis, and restored the autophagic flux. In the diabetic rat model, Nec-1 (1.65 mg/kg) treatment for 4 months markedly alleviated myocardial fibrosis, downregulated autophagic related proteins, and improved cardiac systolic and diastolic function. In conclusion, HGF induces myocardial fibrosis and cardiac dysfunction by activating the RIPK1-RIPK3 pathway and by impairing the autophagic flux, which is obviated by the pharmacological and genetic inhibition of RIPK1/RIPK3.

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Functional suppression of Ripk1 blocks the NF-κB signaling pathway and induces neuron autophagy after traumatic brain injury

Cited by 24 publications

References 26 publications

Elevated Expression of The Rhythm Gene NFIL3 Promotes The Progression of TNBC By Activating NF-κB Signaling Through Suppression of NFKBIA Transcription

Elevated Expression of The Rhythm Gene NFIL3 Promotes The Progression of TNBC By Activating NF-κB Signaling Through Suppression of NFKBIA Transcription

Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts

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