Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling

Tikhanovich, Irina; Kuravi, Sudhakiranmayi; Artigues, Antonio; Villar, María T.; Dorko, Kenneth; Nawabi, Atta; Roberts, Benjamin; Weinman, Steven A.

doi:10.1074/jbc.m115.653543

Cited by 60 publications

(57 citation statements)

References 29 publications

(34 reference statements)

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“…One of the mechanisms by which ethanol exacerbates HCV pathogenesis is via an impaired methylation-dependent interferon signaling in hepatocytes that prevents protective antiviral interferon-stimulated gene activation (17). The role of methylation-dependent dysregulation of innate immunity by ethanol in HCV-infected liver cells has also been shown by others (54). The deficiency in innate immunity suggests that the level of HCV RNA should at least be doubled in alcohol-exposed liver cells.…”

Section: Discussionmentioning

confidence: 89%

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Ganesan

Natarajan

Zhang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Alcohol consumption exacerbates hepatitis C virus (HCV) pathogenesis and promotes disease progression, although the mechanisms are not quite clear. We have previously observed that acetaldehyde (Ach) continuously produced by the acetaldehyde-generating system (AGS), temporarily enhanced HCV RNA levels, followed by a decrease to normal or lower levels, which corresponded to apoptosis induction. Here, we studied whether Ach-induced apoptosis caused depletion of HCV-infected cells and what role apoptotic bodies (AB) play in HCV-alcohol crosstalk. In liver cells exposed to AGS, we observed the induction of miR-122 and miR-34a. As miR-34a has been associated with apoptotic signaling and miR-122 with HCV replication, these findings may suggest that cells with intensive viral replication undergo apoptosis. Furthermore, when AGS-induced apoptosis was blocked by a pan-caspase inhibitor, the expression of HCV RNA was not changed. AB from HCV-infected cells contained HCV core protein and the assembled HCV particle that infect intact hepatocytes, thereby promoting the spread of infection. In addition, AB are captured by macrophages to switch their cytokine profile to the proinflammatory one. Macrophages exposed to HCV ϩ AB expressed more IL-1␤, IL-18, IL-6, and IL-10 mRNAs compared with those exposed to HCV Ϫ AB. The generation of AB from AGS-treated HCV-infected cells even enhanced the induction of aforementioned cytokines. We conclude that HCV and alcohol metabolites trigger the formation of AB containing HCV particles. The consequent spread of HCV to neighboring hepatocytes via infected AB, as well as the induction of liver inflammation by AB-mediated macrophage activation potentially exacerbate the HCV infection course by alcohol and worsen disease progression. HCV RNA; acetaldehyde; apoptosis; hepatocytes; macrophages ALCOHOL EXPOSURE EXACERBATES hepatitis C virus (HCV) infection severity, increases liver inflammation, and potentiates liver injury progression. However, the pathogenesis of HCV-alcohol interactions is not clear yet. The major difficulty in HCValcohol studies is related to the lack of adequate models that can recapitulate both viral replication and ethanol metabolism-two important features that potentiate liver injury progression in alcohol-abusing HCV patients. Human liver cell lines permissive for HCV (Huh7.5 or Huh 7.5.1) that are currently used for HCV-alcohol-related in vitro studies do not metabolize ethanol, while ethanol-metabolizing rodent liver cells cannot support HCV replication. Studies conducted with isolated human hepatocytes also have failed, since these cells require at least 4 -5 days to become infected with HCV; however, by this time, hepatocytes lose the expression and functional activity of CYP2E1 and alcohol dehydrogenase (ADH), the main ethanol-metabolizing enzymes (47). In vivo models of HCV infection are also questionable, since small rodents cannot be infected with human HCV, and they only transgenically express HCV proteins, in the absence of replicating virus. The best option i...

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Section: Discussionmentioning

confidence: 89%

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Ganesan

Natarajan

Zhang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Given that type I PRMTs are known to control NF-κB target genes (18)(19)(20)(21)(22), we investigated whether Rel proteins are modified by asymmetric arginine dimethylation. We tested PRMT1, PRMT4, and PRMT6, all of which are present in the nucleus and modify histones, for their ability to methylate the RelA subunit of NF-κB.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that PRMT1 and PRMT5 methylate SPT5 and repress its promoter association and interaction with RNApol II, resulting in a lower rate of transcriptional elongation. It also has been reported that under basal conditions, the ubiquitin ligase activity of TNF receptorassociated factor 6 is impaired by PRMT1-mediated methylation, resulting in inhibition of NF-κB (22). It is likely that PRMT1-mediated regulation of NF-κB target genes requires methylation of other proteins involved in transcription or upstream of NF-κB.…”

Section: (7)mentioning

confidence: 99%

“…In addition to PRMT5, several type I PRMTs, including PRMT1, PRMT2, PRMT4, and PRMT6, have been shown to coregulate NF-κB target genes (18)(19)(20)(21)(22); however, it remains unclear whether Rel proteins are also modified by type I PRMTs that methylate arginines asymmetrically, thereby leading to the formation of asymmetric ω-N G ,N G -dimethylarginine (ADMA).…”

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confidence: 99%

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Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Reintjes

Fuchs

Kremser

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB-activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-κB target genes in response to TNFα. Molecular dynamics simulations of the DNA-bound RelA:p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA-NF-κB complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNFα/NF-κB signaling.arginine methylation | genes | TNFα | NF-κB

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“…Although suppression of STAT1 methylation was mainly attributed to PRMT1 dysfunction, we cannot exclude that HCV-induced demethylation of STAT1 also regulates IFNα signaling. In fact, it has been shown recently that the methylation of another innate immunity regulator, TNF receptor-associated factor 6 (TRAF6), is partially controlled by demethylase Jumonji domain-containing protein 6 (JMJD6) [8]. The JMJD6 is a non-heme Fe(II) 2-oxoglutarate (2OG)-dependent oxygenase with bifunctional enzymatic activities, arginine demethylase and lysyl hydroxylase [9,10].…”

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confidence: 99%

Demethylase JMJD6 as a regulator of innate immunity in HCV-associated liver injury

Osna

2017

Int J Hepatobiliary Pancreat Dis

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Hepatitis C virus (HCV) infection causes the dysfunction of innate immunity in hepatocytes, the primary sites of viral replication. Anti-viral protection of hepatocytes requires the induction of interferon alpha (IFNα) signaling that activates interferon-stimulated genes (ISGs) to control viral replication and spread. The IFNα signaling is initiated by endogenous IFNα released by non-parenchymal liver cells (macrophages, dendritic cells) upon sensing the virus. Binding of IFNα to surface receptors on hepatocytes activates the JAK-STAT pathway. To attach to DNA and induce protective ISGs, STAT1 requires protein methyl transferase 1 (PRMT1)-mediated arginine methylation [1].While protein expression level is regulated by histone methylation/acetylation, multiple methyltransferases induce the methylation of proteins on various residues (arginine, lysine, etc). In the liver, activities of many methyltransferases are regulated by the methionine metabolic pathway, namely, by the changes in the ratio between the methyl donor, S-adenosyl methionine (SAM) and its toxic metabolite, S-adenosylhomocysteine (SAH). Alcohol and HCV decreases SAM: SAH ratio [2-4], suggesting that SAM-dependent PRMT1 and subsequent STAT1 methylation in hepatocytes may be altered due to HCV-and alcohol-induced SAM insufficiency. Indeed, in infected hepatocytes, methylation of STAT1 on Arg-31 is impaired by HCV [5,6] decrease STAT1 methylation, thereby enhancing PIAS1-STAT1 interactions to prevent STAT1 binding to DNA [7]. Although suppression of STAT1 methylation was mainly attributed to PRMT1 dysfunction, we cannot exclude that HCV-induced demethylation of STAT1 also regulates IFNα signaling. In fact, it has been shown recently that the methylation of another innate immunity regulator, TNF receptor-associated factor 6 (TRAF6), is partially controlled by demethylase Jumonji domain-containing protein 6 (JMJD6) [8]. The JMJD6 is a non-heme Fe(II) 2-oxoglutarate (2OG)-dependent oxygenase with bifunctional enzymatic activities, arginine demethylase and lysyl hydroxylase [9,10]. Importantly, STAT1 has never been characterized as a JMJD6 target, and the role of this enzyme in STAT1 methylation in hepatocytes has never been investigated in viral hepatitis.In our laboratory, we studied whether arginine methylation of STAT1 is modulated by JMJD6 and whether there is a functional link between HCV replication and JMJD6 levels in IFNα-induced anti-viral protection via the JAK-STAT1 pathway in hepatocytes. The modulation of JMJD6 levels by viruses has been already demonstrated in literature [11,12], but nothing is known about the role of JMJD6 in HCV-infection. In our preliminary (unpublished) experiments, we found that in Huh 7.5 (hepatoma) cells, JMJD6 overexpression reduced STAT1 methylation on arginine residue, while JMJD6 silencing increased STAT1 methylation. We also found that JMJD6 suppression enhanced activation ISGs and suppressed HCV RNA; however, there was a negative impact of JMJD6 overexpression on innate immunity (unpublished data). Previously, ...

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Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling

Cited by 60 publications

References 29 publications

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Demethylase JMJD6 as a regulator of innate immunity in HCV-associated liver injury

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