Gcn5 Modulates the Cellular Response to Oxidative Stress and Histone Deacetylase Inhibition

Gaupel, Ann-Christin; Begley, Thomas J.; Tenniswood, Martin

doi:10.1002/jcb.25153

Cited by 26 publications

(21 citation statements)

References 35 publications

(39 reference statements)

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“…Lysine acetylation is a reversible process catalyzed by acetyltransferases and deacetylases (9). To identify the acetyltransferase responsible for TyrRS acetylation, we overexpressed p300/CBP-associated factor (PCAF), Tip60, and GCN5 into HEK293T cells, because PCAF, Tip60, and GCN5 have been shown to respond to oxidative stress (22)(23)(24)(25), and found that the acetylation of TyrRS was elevated only after the ectopic expression of PCAF, not the other acetyltransferases ( Fig. 2A).…”

Section: Significancementioning

confidence: 99%

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Cao

Xiao

et al. 2017

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

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Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential aminoacylation function in protein synthesis. Recently, TyrRS has been shown to translocate to the nucleus and protect against DNA damage due to oxidative stress. However, the mechanism of TyrRS nuclear localization has not yet been determined. Herein, we report that TyrRS becomes highly acetylated in response to oxidative stress, which promotes nuclear translocation. Moreover, p300/ CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, regulate the nuclear localization of TyrRS in an acetylation-dependent manner. Oxidative stress increases the level of PCAF and decreases the level of SIRT1 and deacetylase activity, all of which promote the nuclear translocation of hyperacetylated TyrRS. Furthermore, TyrRS is primarily acetylated on the K244 residue near the nuclear localization signal (NLS), and acetylation inhibits the aminoacylation activity of TyrRS. Molecular dynamics simulations have shown that the in silico acetylation of K244 induces conformational changes in TyrRS near the NLS, which may promote the nuclear translocation of acetylated TyrRS. Herein, we show that the acetylated K244 residue of TyrRS protects against DNA damage in mammalian cells and zebrafish by activating DNA repair genes downstream of transcription factor E2F1. Our study reveals a previously unknown mechanism by which acetylation regulates an aminoacyl-tRNA synthetase, thus affecting the repair pathways for damaged DNA.

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Section: Significancementioning

confidence: 99%

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Cao

Xiao

et al. 2017

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

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“…However, we cannot exclude the possibility that complexes other than SAGA, such as the SAGA-like complex (27,38), components of which are shared with SAGA, mediate transcriptional regulation of dcl2. Roles of the SAGA complex in abiotic stress responses have been extensively studied in other organisms, particularly in yeast (34,39,40), but rarely in biotic stress conditions, including virus infection. This is an example of SAGA's involvement in an antiviral response.…”

Section: Saga Mediates Virus-responsive Induction Of Rnai Key Genesmentioning

confidence: 99%

SAGA complex mediates the transcriptional up-regulation of antiviral RNA silencing

Andika

Jamal

Kondō

et al. 2017

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

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Pathogen recognition and transcriptional activation of defenserelated genes are crucial steps in cellular defense responses. RNA silencing (RNAi) functions as an antiviral defense in eukaryotic organisms. Several RNAi-related genes are known to be transcriptionally up-regulated upon virus infection in some host organisms, but little is known about their induction mechanism. A phytopathogenic ascomycete, Cryphonectria parasitica (chestnut blight fungus), provides a particularly advantageous system to study RNAi activation, because its infection by certain RNA viruses induces the transcription of dicer-like 2 (dcl2) and argonaute-like 2 (agl2), two major RNAi players. To identify cellular factors governing activation of antiviral RNAi in C. parasitica, we developed a screening protocol entailing multiple transformations of the fungus with cDNA of a hypovirus mutant lacking the RNAi suppressor (CHV1-Δp69), a reporter construct with a GFP gene driven by the dcl2 promoter, and a random mutagenic construct. Screening for GFP-negative colonies allowed the identification of sgf73, a component of the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, a well-known transcriptional coactivator. Knockout of other SAGA components showed that the histone acetyltransferase module regulates transcriptional induction of dcl2 and agl2, whereas histone deubiquitinase mediates regulation of agl2 but not dcl2. Interestingly, full-scale induction of agl2 and dcl2 by CHV1-Δp69 required both DCL2 and AGL2, whereas that by another RNA virus, mycoreovirus 1, required only DCL2, uncovering additional roles for DCL2 and AGL2 in viral recognition and/or RNAi activation. Overall, these results provide insight into the mechanism of RNAi activation.Cryphonectria parasitica | hypovirus | RNAi | mycovirus | antiviral defense

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“…The results demonstrate that UTI can effectively prevent liver injury, reduce proinflammatory cytokines, relieve oxidative stress, and strengthen the antioxidant defense system. Oxidative stress can activate molecular pathways that provoke inflammation and directly cause tissue damage . This type of tissue injury is considered as one of the most important mechanisms in the progression of multiple organ failure due to septic shock.…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress can activate molecular pathways that provoke inflammation and directly cause tissue damage. 21 This type of tissue injury is considered as one of the most important mechanisms in the progression of multiple organ failure due to septic shock. Our data showed that the changes in serum liver function parameters can reflect the pathological changes of the liver.…”

Section: Discussionmentioning

confidence: 99%

Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model

Song

Miao

et al. 2018

J of Cellular Biochemistry

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Sepsis is a syndrome of life-threatening multiorgan dysfunction caused by host response dysregulation to infection. Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide-induced sepsis. However, little is known about the mechanism underlying its effects on sepsis. In the current study, we investigated the protective effect of UTI on liver injury in a cecal ligation and puncture (CLP)-induced sepsis of C57BL/6 mouse model and explored the possible mechanisms. Mice underwent CLP as sepsis models and were randomized into five groups including the sham group, UTI group, CLP group, UTI-L group, and UTI-H group. UTI was intraperitoneally administered at doses of UTI 1500 U/100 g (UTI-L group) or 3000 U/100 g (UTI-H group), before CLP. The mice were killed, and immunohistochemical changes, cytokine levels, and antioxidant enzyme activities were detected. Our results showed that UTI ameliorated CLP-mediated increases in serum aspartate aminotransferase and alanine aminotransferase activities, histological activity index, degenerative region ratio, and infiltrated inflammatory cell numbers. Moreover, UTI also decreased nitrotyrosine and 4-hydroxynonenal, activated caspase-3, and activated poly (ADP-ribose) polymerase (PARP) levels and inhibited the mitogen-activated protein kinase pathway activation in liver tissues. Our results indicated that UTI could inhibit CLP-induced liver injury by suppressing inflammation and oxidation. Our results indicated that UTI may serve as a potential therapeutic agent for sepsis.

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Gcn5 Modulates the Cellular Response to Oxidative Stress and Histone Deacetylase Inhibition

Cited by 26 publications

References 35 publications

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

SAGA complex mediates the transcriptional up-regulation of antiviral RNA silencing

Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model

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