Proinflammatory Stimuli Induce IKKα-Mediated Phosphorylation of PIAS1 to Restrict Inflammation and Immunity

Liu, Bin; Yang, Yonghui; Chernishof, Vasili; Loo, Rachel R. Ogorzalek; Jang, Hyunduk; Tahk, Samuel; Yang, Randy; Mink, Sheldon; Shultz, David; Bellone, Clifford J.; Loo, Joseph A.; Shuai, Ke

doi:10.1016/j.cell.2007.03.056

Cited by 150 publications

(146 citation statements)

References 26 publications

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“…NF-κB plays an important role in a wide spectrum of cellular responses and needs to be regulated properly at multilevels; inappropriate regulation of NF-κB is involved in a number of human diseases. Besides the well-characterized feedback pathway whereby newly synthesized IκB-α serves to shut off the signal [28], recent studies have gradually revealed a series of molecules, including A20 [29,30], CYLD [31,32], Twist [33], β-arrestins [34,35] and PIAS [36,37], all of which are capable of regulating NF-κB activity negatively. Here our work revealed that Dvl protein also serves as a negative regulator of NF-κB signaling.…”

Section: Discussionmentioning

confidence: 99%

Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

Deng

Wang

et al. 2010

Cell Res

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Dishevelled (Dvl) is a highly conserved protein family that plays an important role in mediating Wnt signaling from membrane to cytoplasm. Recently we reported that Dvl also functions in the nucleus by stabilizing the β-catenin/TCFs transcriptional complex. Here we describe that Dvl may function as a repressor of NF-κB. Our data show that Dvl directly binds to p65 and their interaction occurs in the nucleus. Dvl expression inhibits p65-mediated or TNF-α-stimulated activation of the NF-κB dependent reporter. This action of Dvl, however, is not dependent on Wnt or its downstream effector β-catenin. Chromatin immunoprecipitation assay shows that recruitment of p65 to the promoters of NF-κB target genes is significantly enhanced when expression of Dvl is knocked down. Consistently, the expression level of a subset of NF-κB target genes is also increased after knock-down of Dvl. Moreover, our data suggest that Dvl may relieve the anti-apoptotic effect of NF-κB, thus play a role in promoting apoptosis. Therefore, this work demonstrates a novel function of Dvl in modulating NF-κB-regulated gene transcription.

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Section: Discussionmentioning

confidence: 99%

Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

Deng

Wang

et al. 2010

Cell Res

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“…[21][22][23] We also found that IKKa expression levels were higher in skin papillomas, a benign form of skin tumors, compared with normal skin in C57BL6 mice. 24 Approximately, only 3-5% of the papillomas progress to malignant carcinomas, but the rest eventually regress in C57BL6 mice.…”

mentioning

confidence: 61%

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

et al. 2011

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Inhibitor of nuclear factor jB kinase-a (IKKa) is required for maintaining skin homeostasis and preventing skin tumorigenesis. However, its signaling has not been extensively investigated. In the present study, we generated two mouse lines that expressed different levels of transgenic IKKa in the basal epidermis under the control of keratin-5 promoter and further evaluated their effects on the major pathways of inflammation, proliferation, and differentiation in the skin. Regardless of the transgenic IKKa levels, the mice develop normally. Because IKKa deletion in keratinocytes blocks terminal differentiation and induces epidermal hyperplasia and skin inflammation, we depleted the endogenous IKKa in these transgenic mice and found that the transgenic IKKa represses epidermal thickness and induces terminal differentiation in a dose-dependent manner. Also, transgenic IKKa was found to elevate expression of Max dimer protein 1 (Mad1) and ovo-like 1, c-Myc antagonists, but repress activities of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Jun-amino-terminal kinases, c-Jun, signal transducer and activator of transcription 3 (Stat3), and growth factor levels in a dose-dependent fashion in the skin. Moreover, EGFR reduction represses IKKa deletion-induced excessive ERK, Stat3 and c-Jun activities, and skin inflammation. These new findings indicate that elevated IKKa expression not only represses epidermal thickness and induces terminal differentiation, but also suppresses skin inflammation by an integrated loop. Thus, IKKa maintains skin homeostasis through a broad range of signaling pathways.

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“…S5) indicating that PRMT1 does not control the sumoylation activity of PIAS1. Moreover, overexpression of the sumoylation-deficient PIAS1 mutant W372A (Liu et al 2007) revealed a similar repressive effect on the IFN induction of the same STAT1 target genes as wild-type PIAS1 (Supplemental Fig. S6).…”

Section: R E T R a C T E Dmentioning

confidence: 92%

“…Similar to the regulation of PIAS1 by PRMT1, S90 phosphorylation was needed to allow promoter recruitment of PIAS1 in NF-kB-activated transcription and resulted in the detachment of NF-kB from its targets. In contrast to the regulation by PRMT1, the Sumo E3-ligase activity was necessary for the repressive function of PIAS1, since a sumoylation-deficient PIAS1 mutant was defective in S90 phosphorylation (Liu et al 2007). Interestingly, we did not find phosphorylated PIAS1 species in response to IFNg treatment (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported recently that PIAS1 is phosphorylated at Ser 90 by the IKKa kinase particularly in response to TNFa and LPS stimulation, and that this modification is required to repress the NF-kB/STAT1 activity (Liu et al 2007). Similar to the regulation of PIAS1 by PRMT1, S90 phosphorylation was needed to allow promoter recruitment of PIAS1 in NF-kB-activated transcription and resulted in the detachment of NF-kB from its targets.…”

Section: Discussionmentioning

confidence: 99%

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PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling

Weber¹,

Maass²,

Schuemann³

et al. 2009

Genes Dev.

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To elucidate the function of the transcriptional coregulator PRMT1 (protein arginine methyltranferase 1) in interferon (IFN) signaling, we investigated the expression of STAT1 (signal transducer and activator of transcription) target genes in PRMT1-depleted cells. We show here that PRMT1 represses a subset of IFNginducible STAT1 target genes in a methyltransferase-dependent manner. These genes are also regulated by the STAT1 inhibitor PIAS1 (protein inhibitor of activated STAT1). PIAS1 is arginine methylated by PRMT1 in vitro as well as in vivo upon IFN treatment. Mutational and mass spectrometric analysis of PIAS1 identifies Arg 303 as the single methylation site. Using both methylation-deficient and methylation-mimicking mutants, we find that arginine methylation of PIAS1 is essential for the repressive function of PRMT1 in IFN-dependent transcription and for the recruitment of PIAS1 to STAT1 target gene promoters in the late phase of the IFN response. Methylation-dependent promoter recruitment of PIAS1 results in the release of STAT1 and coincides with the decline of STAT1-activated transcription. Accordingly, knockdown of PRMT1 or PIAS1 enhances the antiproliferative effect of IFNg. Our findings identify PRMT1 as a novel and crucial negative regulator of STAT1 activation that controls PIAS1-mediated repression by arginine methylation.[Keywords: Transcriptional repression; interferon signaling; STAT1; PIAS1; PRMT1; arginine methylation] Supplemental material is available at http://www.genesdev.org.

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Proinflammatory Stimuli Induce IKKα-Mediated Phosphorylation of PIAS1 to Restrict Inflammation and Immunity

Cited by 150 publications

References 26 publications

Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling

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