NIK as a Druggable Mediator of Tissue Injury

Valiño-Rivas, Lara; Vaquero, Juan J.; Sucunza, David; Gutiérrez, Sara; Sanz, Ana B.; Fresno, Manuel; Ortíz, Alberto; Sánchez-Niño, María D.

doi:10.1016/j.molmed.2019.02.005

Cited by 35 publications

(25 citation statements)

References 96 publications

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“…The top 20 significant biological processes are summarized in Table 1 . The top process that was significant even after correction using the false discovery rate (FDR) was NIK (NF-KB [nuclear factor-kappa B] inducing kinase, also termed MAP3K14, mitogen-activated protein kinase kinase kinase 14)/NF-ΚB signaling, which reportedly has an essential role in the immune response and carcinogenesis (Valiño-Rivas et al 2019 ). Furthermore, four and two processes in Table 1 were involved in the NF-ΚB signaling pathway (GO:0038061, GO:0007250, GO:1901222 and GO:1901224) and in the Wnt signaling pathway (GO:0060071 and GO:0090263), respectively.…”

Section: Resultsmentioning

confidence: 99%

Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Tian

Arai

Makiuchi

et al. 2020

J Cancer Res Clin Oncol

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The aim of this study was to investigate DNA methylation alterations in non-alcoholic steatohepatitis (NASH)related hepatocellular carcinomas (HCCs). Methods Genome-wide DNA methylation analysis was performed using the Infinium Human Methylation 450 K BeadChip, and levels of mRNA expression were analyzed by quantitative reverse transcription-PCR. Results Compared to 36 samples of normal control liver tissue (C), DNA methylation alterations were observed on 19,281 probes in 22 samples of cancerous tissue (T) obtained from patients showing histological features compatible with NASH in their non-cancerous liver tissue (N). Among those probes, 1396 were located within CpG islands or their shores and shelves, designed around the transcription start sites of 726 genes. In representative genes, such as DCAF4L2, CKLF, TRIM4, PRC1, UBE2C and TUBA1B, both DNA hypomethylation and mRNA overexpression were observed in T samples relative to C samples, and the levels of DNA methylation and mRNA expression were inversely correlated with each other. DNA hypomethylation occurred even in N samples at the precancerous NASH stage, and this was inherited by or further strengthened in T samples. DNA hypomethylation of DCAF4L2, CKLF and UBE2C was observed in both NASH-related and viral hepatitis-related HCCs, whereas that of TRIM4, PRC1 and TUBA1B occurred in a NASH-related HCC-specific manner. DNA hypomethylation and/or mRNA overexpression of these genes was frequently associated with the necroinflammatory grade of NASH and was correlated with poorer tumor differentiation. Conclusion DNA methylation alterations may occur under the necroinflammatory conditions characteristic of NASH and participate in NASH-related hepatocarcinogenesis through aberrant expression of tumor-related genes.

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Section: Resultsmentioning

confidence: 99%

Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Tian

Arai

Makiuchi

et al. 2020

J Cancer Res Clin Oncol

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“…TWEAK is a proinflammatory cytokine of the TNF superfamily that promotes AKI and CKD [67,68]. A key feature of the TWEAK cytokine is that, contrary to TNF, it recruits the NIK-mediated, non-canonical pathway for activation of the NFκB transcription factor in kidney cells on top of the canonical pathway for NFκB activation [69][70][71][72][73]. NFκB is a key proinflammatory transcription factor that also downregulates kidney protective molecules [74].…”

Section: Kidney Inflammationmentioning

confidence: 99%

Chronodisruption: A Poorly Recognized Feature of CKD

Carriazo

Ramos

Sanz

et al. 2020

Toxins

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Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic.

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“…As an important regulatory protein, the function of NIK is not limited to innate immunity. NIK is also reported to be involved in tissue injury (47) and tumor development (48,49). Therefore, results presented in this study may facilitate more in-depth studies in the future for a comprehensive understanding of the possible function of NIK in fish.…”

Section: Discussionmentioning

confidence: 67%

Zebrafish NIK Mediates IFN Induction by Regulating Activation of IRF3 and NF-κB

Chen

Yao

et al. 2020

The Journal of Immunology

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Type I IFN mediates the innate immune system to provide defense against viral infections. NF-κB–inducing kinase (NIK) potentiates the basal activation of endogenous STING, which facilitates the recruitment of TBK1 with the ectopically expressed IRF3 to induce IFN production. Moreover, NIK phosphorylates IKKα and confers its ability to phosphorylate p100 (also known as NF-κB2) in mammals. Our study demonstrated that NIK plays a critical role in IFN production in teleost fish. It was found that NIK interacts with IKKα in the cytoplasm and that IKKα phosphorylates the NIK at the residue Thr432, which is different from the mammals. Overexpression of NIK caused the activation of IRF3 and NF-κB, which in turn led to the production of IFN and IFN-stimulated genes (ISGs). Furthermore, the ectopic expression of NIK was observed to be associated with a reduced replication of the fish virus, whereas silencing of endogenous NIK had an opposite effect in vitro. Furthermore, NIK knockdown significantly reduced the expression of IFN and key ISGs in zebrafish larvae after spring viremia of carp virus infection. Additionally, the replication of spring viremia of carp virus was enhanced in NIK knockdown zebrafish larvae, leading to a lower survival rate. In summary, our findings revealed a previously undescribed function of NIK in activating IFN and ISGs as a host antiviral response. These findings may facilitate the establishment of antiviral therapy to combat fish viruses.

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NIK as a Druggable Mediator of Tissue Injury

Cited by 35 publications

References 96 publications

Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Chronodisruption: A Poorly Recognized Feature of CKD

Zebrafish NIK Mediates IFN Induction by Regulating Activation of IRF3 and NF-κB

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