PARIS reprograms glucose metabolism by HIF-1α induction in dopaminergic neurodegeneration

Kang, Hyo; Jo, Areum; Kim, Hyein; Khang, Rin; Lee, Jiyeong; Kim, Hanna; Park, Chi-Hu; Choi, Jeong‐Yun; Lee, Yong Kyu; Shin, Joo‐Ho

doi:10.1016/j.bbrc.2017.12.147

Cited by 15 publications

(5 citation statements)

References 26 publications

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“…The ZNF746 protein level itself is controlled by parkin whose E3 ubiquitin ligase activity marks ZNF746 for proteasomal degradation in a phosphorylation-dependent manner [37]. In Parkinson’s disease, parkin loss-of-function mutants lead to ZNF746 overexpression with disturbance of mitochondrial homeostasis and energy metabolism and concomitant loss of dopaminergic neurons [35, 38, 39]. The sumoylation status of ZNF746 modulates its transcriptional repressor activity towards the PGC-1α promoter in a complex, not fully understood manner [40].…”

Section: Introductionmentioning

confidence: 99%

DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression

Chiblak

Steinbeck

Thiesen

et al. 2019

BMC Mol and Cell Biol

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BackgroundZNF746 and ZNF777 belong to a subset of the large Krüppel-associated box (KRAB) zinc finger (ZNF) transcription factor family. They contain, like four other members in human, an additional conserved domain, the “domain of unknown function 3669” (DUF3669). Previous work on members of this subfamily suggested involvement in transcriptional regulation and aberrant ZNF746 overexpression leads to neuronal cell death in Parkinson’s disease.ResultsHere we demonstrate that N-terminal protein segments of the ZNF746a major isoform and ZNF777 act in concert to exert moderate transcriptional repression activities. Full potency depended on the intact configuration consisting of DUF3669, a variant KRAB domain and adjacent sequences. While DUF3669 contributes an intrinsic weak inhibitory activity, the isolated KRAB-AB domains did not repress. Importantly, DUF3669 provides a novel protein-protein interaction interface and mediates direct physical interaction between the members of the subfamily in oligomers. The ZNF746 protein segment encoded by exons 5 and 6 boosted repressor potency, potentially due to the presence of an acceptor lysine for sumoylation at K189. Repressor activity of the potent canonical ZNF10 KRAB domain was not augmented by heterologous transfer of DUF3669, pointing to the importance of context for DUF3669’s impact on transcription. Neither ZNF746a nor ZNF777 protein segments stably associated with TRIM28 within cells. Isoform ZNF746b that contains, unlike the major isoform, a full-length KRAB-A subdomain, displayed substantially increased repressor potency. This increase is due to canonical mechanisms known for KRAB domains since it did not take place in HAP1 knockout models of TRIM28 and SETDB1. A glycine to glutamic acid replacement that complies with a bona fide conserved “MLE” sequence within KRAB-A led to a further strong gain in repressor potency to levels comparable to those of the canonical ZNF10 KRAB domain. Each gain of repressive activity was accompanied by an enhanced interaction with TRIM28 protein.ConclusionDUF3669 adds a protein-protein interaction surface to a subgroup of KRAB-ZNF proteins within an N-terminal configuration with variant KRAB and adjacent sequences likely regulated by sumoylation. DUF3669 contributes to transcriptional repression strength and its homo- and hetero-oligomerization characteristics probably extended the regulatory repertoire of KRAB-ZNF transcription factors during amniote evolution.

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Section: Introductionmentioning

confidence: 99%

DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression

Chiblak

Steinbeck

Thiesen

et al. 2019

BMC Mol and Cell Biol

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“…The inactivation of parkin leads to mitochondrial dysregulation by PARIS accumulation and PGC‐1α suppression (Stevens et al , 2015). Our studies have also demonstrated that PARIS downregulates the production of ribosomal RNA and transketolase through the occupation of their promoters (Kang & Shin, 2015; Kim et al , 2017; Kang et al , 2018).…”

Section: Introductionmentioning

confidence: 79%

PARIS undergoes liquid–liquid phase separation and poly(ADP‐ribose)‐mediated solidification

Kang,

Park,

et al. 2023

EMBO Reports

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ZNF746 was identified as parkin‐interacting substrate (PARIS). Investigating its pathophysiological properties, we find that PARIS undergoes liquid–liquid phase separation (LLPS) and amorphous solid formation. The N‐terminal low complexity domain 1 (LCD1) of PARIS is required for LLPS, whereas the C‐terminal prion‐like domain (PrLD) drives the transition from liquid to solid phase. In addition, we observe that poly(ADP‐ribose) (PAR) strongly binds to the C‐terminus of PARIS near the PrLD, accelerating its LLPS and solidification. N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG)‐induced PAR formation leads to PARIS oligomerization in human iPSC‐derived dopaminergic neurons that is prevented by the PARP inhibitor, ABT‐888. Furthermore, SDS‐resistant PARIS species are observed in the substantia nigra (SN) of aged mice overexpressing wild‐type PARIS, but not with a PAR binding‐deficient PARIS mutant. PARIS solidification is also found in the SN of mice injected with preformed fibrils of α‐synuclein (α‐syn PFF) and adult mice with a conditional knockout (KO) of parkin, but not if α‐syn PFF is injected into mice deficient for PARP1. Herein, we demonstrate that PARIS undergoes LLPS and PAR‐mediated solidification in models of Parkinson's disease.

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“…S4E and F). Mgat1 is associated with lipid metabolism and obesity ( 8, 9 ), Tkt regulates glucose metabolism ( 10, 11 ), and Pik3cd is involved in lipid metabolism and diabetes ( 12, 13 ). These results suggest that the altered methylation in HFD oocytes is partly transmitted to F1 livers via oocytes, and abnormal methylation may be a reason for the disturbed metabolism of HF1.…”

Section: Resultsmentioning

confidence: 99%

Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs

Chao,

Lu,

et al. 2024

Preprint

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Maternal obesity has deleterious effects on oocyte genome methylation establishment, yet the underlying mechanisms remain unclear. In the present study, we first find that maternal obesity induced by high-fat diet (HFD) disturbs genomic methylation in oocytes, and at least a part of the altered methylation is transmitted to F2 oocytes and livers via females. We further identified that altered metabolites such as methionine and melatonin may play a key role in the re-methylation establishment in oocytes of obese mice. Exogenous melatonin treatment significantly reduces the hyper-methylation of HFD oocytes. The higher expression of DNMT3a and DNMT1 in HFD oocytes is also decreased by melatonin supplement, which may be mediated by cAMP/PKA/CREB pathway. These results suggest that maternal obesity-induced genomic methylation alterations in oocytes, can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes via increasing the expression of DNMTs mediated by cAMP/PKA/CREB pathway.

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PARIS reprograms glucose metabolism by HIF-1α induction in dopaminergic neurodegeneration

Cited by 15 publications

References 26 publications

DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression

DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression

PARIS undergoes liquid–liquid phase separation and poly(ADP‐ribose)‐mediated solidification

Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs

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