Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality

Ahmed, Shaimaa; Bott, Debbie; Gomez, Alvaro; Tamblyn, Laura; Rasheed, Adil; Cho, Tiffany; MacPherson, Laura; Sugamori, Kim S.; Yang, S.Y. Cindy; Grant, Denis M.; Cummins, Carolyn L.; Matthews, Jason

doi:10.1074/jbc.m115.660100

Cited by 53 publications

(101 citation statements)

References 56 publications

(72 reference statements)

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“…At 92 days, total PKM protein levels increased 2.7-fold, matched by a 2.7-fold increase in PKM2 and no change PKM1 (Supplementary Figure 4). A concomitant decrease in pyruvate carboxykinase (PEPCK-C; Pck1) mRNA (2.0-fold at 28 and 92 days) and protein (1.4-fold; P-value ¼ 0.06) with a 4.0-fold increase in AhR enrichment is in line with TCDD-elicited repression of gluconeogenesis (Supplementary Figure 4) (Ahmed et al, 2015).…”

Section: Altered Glucose and Glycogen Metabolismmentioning

confidence: 59%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 mg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1b, -2, -4, -6, and -10, as well as TNF-a and IFN-c, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNASeq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

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Section: Altered Glucose and Glycogen Metabolismmentioning

confidence: 59%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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“…inactive mRNA regulation and miRNA silencing [36] Component of stress granules [17] Viral defense [36] ARTD14 (PARP7, TiPARP) MAR AHR signaling [37][38][39][40] Translation [31] TCCD-induced hepatotoxicity [40] Inhibition of viral replication [31,41] ARTD15 (PARP16) MAR Unfolded protein response [42] Not reported ARTD16 (PARP8) MAR Unclear Not reported ARTD17 (PARP6) MAR Regulates cell cycle progression [43] Inhibits cell proliferation, survival benefit in colorectal cancer [43] SIRT4 MAR Glutamine metabolism [44,45] Tumor-suppressive [45,46] SIRT6 MAR DNA repair [47][48][49] Retrotransposon silencing [50] Tumor suppressive [50][51][52][53][54][55][56][57] and oncogenic functions [58,59] MACROD1 (LRP16) Hydrolase ERα signaling [60,61] AR signaling [62] Promotes cell proliferation [60,62] Metastasis, invasion and survival in gastric and colorectal cancer [63,64].…”

Section: Coast6)mentioning

confidence: 99%

“…Further research has shown that ARTD14 is itself regulating AHR signaling in a negative feedback loop by acting as a transcriptional repressor ( Figure 1) [39]. AHR can also serve as a substrate for ARTD14 [40]. However, whether ARTD14 regulates AHR activity or stability by MARylating waits to be investigated.…”

Section: Artd14 Regulates Ahr Signalingmentioning

confidence: 99%

Intracellular Mono-ADP-Ribosylation in Signaling and Disease

Bütepage

Eckei

Verheugd

et al. 2015

Cells

100

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A key process in the regulation of protein activities and thus cellular signaling pathways is the modification of proteins by post-translational mechanisms. Knowledge about the enzymes (writers and erasers) that attach and remove post-translational modifications, the targets that are modified and the functional consequences elicited by specific modifications, is crucial for understanding cell biological processes. Moreover detailed knowledge about these mechanisms and pathways helps to elucidate the molecular causes of various diseases and in defining potential targets for therapeutic approaches. Intracellular adenosine diphosphate (ADP)-ribosylation refers to the nicotinamide adenine dinucleotide (NAD+)-dependent modification of proteins with ADP-ribose and is catalyzed by enzymes of the ARTD (ADP-ribosyltransferase diphtheria toxin like, also known as PARP) family as well as some members of the Sirtuin family. Poly-ADP-ribosylation is relatively well understood with inhibitors being used as anti-cancer agents. However, the majority of ARTD enzymes and the ADP-ribosylating Sirtuins are restricted to catalyzing mono-ADP-ribosylation. Although writers, readers and erasers of intracellular mono-ADP-ribosylation have been identified only recently, it is becoming more and more evident that this reversible post-translational modification is capable of modulating key intracellular processes and signaling pathways. These include signal transduction mechanisms, stress pathways associated with the endoplasmic reticulum and stress granules, and chromatin-associated processes such as transcription and DNA repair. We hypothesize that mono-ADP-ribosylation controls, through these different pathways, the development of cancer and infectious diseases.

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“…More data may be found on MACROD1, which is also known as leukaemia-related protein 16 or LRP16. MACROD1 has been attributed to a number of functions in the nucleus, such as co-activation of the androgen receptor [83], counteracting PARP7-mediated MARylation in the nucleus [84,85], and activation of NF-kB signalling [86][87][88]. MACROD1 was also reported as an enhancer of oestrogen receptor signalling [89], and is upregulated after stimulation of cells with oestrogen [72,74,90].…”

Section: Macrodomain-containing Hydrolases: Macrod1 Macrod2 and Targ1mentioning

confidence: 99%

“…In pathogenic conditions, such as the presence of a RUNX-MACROD1 fusion protein that was identified in leukaemia [99], the protein likely also localises to the nucleus instead of the mitochondria, as the RUNX fusion will mask the mitochondrial targeting sequence, comparable to the localisation after labelling with an N-terminal GFP tag. Unfortunately, some of the studies investigating MACROD1 have either used N-terminally tagged fusion constructs [84,85,88], or have not stated clearly how the fusion proteins were generated [103]. Furthermore, the majority of applied antibodies show multiple bands in the western blot and, hence, are not suitable for immunohistochemistry (IHC) or immunofluorescence (IF) ( Table 2).…”

Section: Macrod1 In Cancermentioning

confidence: 99%

The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis

Feijs

Cooper

Žaja

2020

Cancers

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Post-translational modifications (PTM) of proteins are crucial for fine-tuning a cell's response to both intracellular and extracellular cues. ADP-ribosylation is a PTM, which occurs in two flavours: modification of a target with multiple ADP-ribose moieties (poly(ADP-ribosyl)ation or PARylation) or with only one unit (MARylation), which are added by the different enzymes of the PARP family (also known as the ARTD family). PARylation has been relatively well-studied, particularly in the DNA damage response. This has resulted in the development of PARP inhibitors such as olaparib, which are increasingly employed in cancer chemotherapeutic approaches. Despite the fact that the majority of PARP enzymes catalyse MARylation, MARylation is not as well understood as PARylation. MARylation is a dynamic process: the enzymes reversing intracellular MARylation of acidic amino acids (MACROD1, MACROD2, and TARG1) were discovered in 2013. Since then, however, little information has been published about their physiological function. MACROD1, MACROD2, and TARG1 have a 'macrodomain' harbouring the catalytic site, but no other domains have been identified. Despite the lack of information regarding their cellular roles, there are a number of studies linking them to cancer. However, some of these publications oppose each other, some rely on poorly-characterised antibodies, or on aberrant localisation of overexpressed rather than native protein. In this review, we critically assess the available literature on a role for the hydrolases in cancer and find that, currently, there is limited evidence for a role for MACROD1, MACROD2, or TARG1 in tumorigenesis.

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Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality

Cited by 53 publications

References 56 publications

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Intracellular Mono-ADP-Ribosylation in Signaling and Disease

The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis

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