Arginine Methylation of FOXO Transcription Factors Inhibits Their Phosphorylation by Akt

Yamagata, Kunio; Daitoku, Hiroaki; Takahashi, Yuta; Namiki, Kana; Hisatake, Koji; Kako, Koichiro; Mukai, Hidehito; Kasuya, Yoshitoshi; Fukamizu, Akiyoshi

doi:10.1016/j.molcel.2008.09.013

Cited by 388 publications

(368 citation statements)

References 39 publications

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“…This sort of multilevel control of FOXO3 function has been demonstrated for arginine methylation and Akt phosphorylation of FOXO1 where Akt phosphorylation is the final determinant of cytosolic translocation but arginine methylation of FOXO1 controls access of Akt to it substrate serine site. 16 It is notable that our studies show that aspartic acid substitution of S-574 alone is sufficient to induce apoptosis, suggesting that once that residue becomes charged, changing acetylation state may not be critical. The exact identity of the gene expression changes responsible for FOXO3-dependent apoptosis has been a matter of debate.…”

Section: Discussionmentioning

confidence: 72%

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Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Zhao

Tikhanovich

et al. 2015

Cell Death Differ

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Forkhead box O3 (FOXO3) is a multispecific transcription factor that is responsible for multiple and conflicting transcriptional programs such as cell survival and apoptosis. The protein is heavily post-translationally modified and there is considerable evidence that post-transcriptional modifications (PTMs) regulate protein stability and nuclear-cytosolic translocation. Much less is known about how FOXO3 PTMs determine the specificity of its transcriptional program. In this study we demonstrate that exposure of hepatocytes to ethanol or exposure of macrophages to lipopolysaccharide (LPS) induces the c-Jun N-terminal kinase (JNK)-dependent phosphorylation of FOXO3 at serine-574. Chromatin immunoprecipitation (ChIP), mRNA and protein measurements demonstrate that p-574-FOXO3 selectively binds to promoters of pro-apoptotic genes but not to other well-described FOXO3 targets. Both unphosphorylated and p-574-FOXO3 bound to the B-cell lymphoma 2 (Bcl-2) promoter, but the unphosphorylated form was a transcriptional activator, whereas p-574-FOXO3 was a transcriptional repressor. The combination of increased TRAIL (TNF-related apoptosis-inducing ligand) and decreased Bcl-2 was both necessary and sufficient to induce apoptosis. LPS treatment of a human monocyte cell line (THP-1) induced FOXO3 S-574 phosphorylation and apoptosis. LPS-induced apoptosis was prevented by knockdown of FOXO3. It was restored by overexpressing wild-type FOXO3 but not by overexpressing a nonphosphorylatable S-574A FOXO3. Expression of an S-574D phosphomimetic form of FOXO3 induced apoptosis even in the absence of LPS. A similar result was obtained with mouse peritoneal macrophages where LPS treatment increased TRAIL, decreased Bcl-2 and induced apoptosis in wild-type but not FOXO3 −/− cells. This work thus demonstrates that S-574 phosphorylation generates a specifically apoptotic form of FOXO3 with decreased transcriptional activity for other well-described FOXO3 functions. Forkhead box O3 (FOXO3) is a multispecific transcription factor that serves as a longevity factor 1,2 and tumor suppressor and is critically involved in multiple seemingly independent biological process including cell-cycle arrest, 3 DNA repair, 4 antioxidant and stress responses, 5 apoptosis, 6 autophagy, glucose metabolism and aging. 7 Its many transcriptional programs are frequently in opposition to each other as it induces apoptosis, yet it is also critical for cell survival and longevity. Although there is considerable information regarding the mechanisms that regulate the nuclear/cytosolic distribution and protein stability of FOXO3, the control mechanisms that regulate transcriptional specificity are poorly understood.FOXO3 function is tightly regulated by multiple posttranslational modifications (PTMs) including phosphorylation, acetylation, ubiquitination and arginine and lysine methylation. Specific PTMs regulate the partitioning of FOXO3 between the cytosol and the nucleus 8-15 and its stability and degradation, 16 but the links between specific PTMs and FOXO3 tran...

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Section: Discussionmentioning

confidence: 72%

“…Specific PTMs regulate the partitioning of FOXO3 between the cytosol and the nucleus [8][9][10][11][12][13][14][15] and its stability and degradation, 16 but the links between specific PTMs and FOXO3 transcriptional specificity are less well understood.…”

mentioning

confidence: 99%

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Zhao

Tikhanovich

et al. 2015

Cell Death Differ

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“…Recent studies from our laboratory have shown that the combination of HCV and alcohol specifically suppresses arginine methylation of FOXO3, 47 and this is expected to make it a better substrate for Akt phosphorylation, causing nuclear export and degradation. 48 Because the effects can be seen in our transgenic mice and infected cells, the HCV structural proteins, particularly core, may play a critical role in FOXO3 modulation. This would not be unexpected because the core protein itself has been implicated as a major cause of HCV-induced oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Tumurbaatar

Tikhanovich

et al. 2013

The American Journal of Pathology

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Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3 À/À mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2 þ/À ) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcoholeinduced liver injury. (Am J Pathol 2013 http://dx

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“…As a transcription factor, FOXO3 regulates expression of several target genes that participate in a series of cellular processes and respond to various cellular stresses (4)(5)(6)(7)(8). Alternatively, different cellular stresses cause variant statuses of posttranslational modifications of FOXO3, such as phosphorylation, ubiquitination, acetylation, and methylation, which in turn regulate the stability or activity of FOXO3 (9)(10)(11)(12)(13)(14).…”

Section: F Orkhead Box O (Foxo) Transcription Factors Homologsmentioning

confidence: 99%

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Xing

Cai

Zhang

et al. 2016

The Journal of Immunology

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Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid–induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.

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Arginine Methylation of FOXO Transcription Factors Inhibits Their Phosphorylation by Akt

Cited by 388 publications

References 39 publications

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

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