Features of the Parkin/Ariadne-like Ubiquitin Ligase, HHARI, That Regulate Its Interaction with the Ubiquitin-conjugating Enzyme, UbcH7

Ardley, Helen C.; Tan, Nancy G.S.; Rose, Stephen A.; Markham, Alexander F.; Robinson, Philip A.

doi:10.1074/jbc.m011028200

Cited by 68 publications

(89 citation statements)

References 46 publications

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“…S2A in the supplemental material). Moreover, a ubiquitination-deficient ARIH1 mutant (C208A mutant) displayed a markedly similar ubiquitination pattern (24). Notably, MS analysis of GFP-ARIH1 immunoprecipitations identified K144 as a ubiquitinated site in ARIH1, yet again, this was not modulated by CP treatment (see Fig.…”

Section: A Ubiquitination Rnai Screen Identifies Cp Response Modulatorsmentioning

confidence: 95%

“…We tested whether the ISGylation or ubiquitination function of ARIH1 was required for its protective role in genotoxic stress. Therefore, we silenced ARIH1 using an siRNA targeting the 3= UTR in U2OS cells expressing either wild-type ARIH1 or a C208A mutant that fails to associate with the E2 enzyme UbcH7, rendering it defective in ubiquitination (whereas interaction with UbcH8 and hence ISGylase activity are intact) (24). Again, ARIH1-silenced cells were more sensitive to CP treatment, although the effect of the transient siRNA was less prominent than stable shRNA-mediated silencing (see Fig.…”

Section: A Ubiquitination Rnai Screen Identifies Cp Response Modulatorsmentioning

confidence: 99%

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The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Stechow

Typas

Carreras-Puigvert

et al. 2015

Molecular and Cellular Biology

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bDNA damage response signaling is crucial for genome maintenance in all organisms and is corrupted in cancer. In an RNA interference (RNAi) screen for (de)ubiquitinases and sumoylases modulating the apoptotic response of embryonic stem (ES) cells to DNA damage, we identified the E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES and cancer cells to genotoxic compounds and ionizing radiation, irrespective of their p53 or caspase-3 status. Expression of wild-type but not ubiquitinase-defective ARIH1 constructs prevented sensitization caused by ARIH1 knockdown. ARIH1 protein abundance increased after DNA damage through attenuation of proteasomal degradation that required ATM signaling. Accumulated ARIH1 associated with 4EHP, and in turn, this competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) underwent increased nondegradative ubiquitination upon DNA damage. Genotoxic stress led to an enrichment of ARIH1 in perinuclear, ribosome-containing regions and triggered 4EHP association with the mRNA 5= cap as well as mRNA translation arrest in an ARIH1-dependent manner. Finally, restoration of DNA damage-induced translation arrest in ARIH1-depleted cells by means of an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. These findings identify ARIH1 as a potent mediator of DNA damage-induced translation arrest that protects stem and cancer cells against genotoxic stress. DNA damage leads to acute toxicity and the accumulation of mutations and chromosomal instability, potentially resulting in malignant transformation (1, 2). To counteract these deleterious effects of DNA damage, the cell is equipped with a highly complex signaling response termed the DNA damage response (DDR). The DDR activates effector components involved in protective pathways, including DNA damage repair, cell cycle arrest, transcription regulation, chromatin remodeling, and cell death (1). The complex of DDR signaling pathways is crucial for the protection of the genome in all organisms. Moreover, understanding DDR signaling in the context of chemical or ionizing radiation-induced DNA damage is important to design improved strategies to combat therapy resistance. In tandem with phosphorylation-mediated signaling, which is largely executed by the phosphoinositol 3-kinase (PI3K)-like kinases ATM, ATR, and DNA-dependent protein kinase (DNA-PK), the checkpoint kinases Chk1 and Chk2, and members of the mitogen-activated protein kinase (MAPK) family (3, 4), protein modifications by ubiquitin and ubiquitin-like moieties are crucial at all levels of the DDR (5).The ubiquitination machinery can form various, differentially interpreted tags, including both degradative (K48-and K11-linked chains) and nondegradative (monoubiquitination and K63-linked chains) signals (6). Furthermore, a growing family of ubiquitin-like modifications, such as SUMO, Nedd8, and ISG15, has been identified, mostly providing nondegradative signals. Multiple enzymes are shared between the ubiquitinat...

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Section: A Ubiquitination Rnai Screen Identifies Cp Response Modulatorsmentioning

confidence: 95%

Section: A Ubiquitination Rnai Screen Identifies Cp Response Modulatorsmentioning

confidence: 99%

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Stechow

Typas

Carreras-Puigvert

et al. 2015

Molecular and Cellular Biology

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“…In both cases, the IBR domain greatly augments this interaction (4). For the RBR protein HHARI, the N-terminal region of the IBR domain and RING1 domain are required for interaction with UbcH7 (30). Based on the enhancement of UbcH7, UbcH8 and substrate binding (synphilin-1, Sept5, SIM2) in the presence of the IBR domain it is clear the T351P mutation would not only disrupt the binding site on the IBR domain surface but would spatially separate the RING1 and RING2 domains due to IBR unfolding.…”

Section: Parkin Ibr Forms a Dual Scissor-like And Gag Knuckle-like Stmentioning

confidence: 99%

Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson's disease

Beasley

Hristova

Shaw

2007

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

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Mutations in Parkin are one of the predominant hereditary factors found in patients suffering from autosomal recessive juvenile Parkinsonism. Parkin is a member of the E3 ubiquitin ligase family that is defined by a tripartite RING1-in-between-ring (IBR)-RING2 motif. In Parkin, the IBR domain has been shown to augment binding of the E2 proteins UbcH7 and UbcH8, and the subsequent ubiquitination of the proteins synphilin-1, Sept5, and SIM2. To facilitate our understanding of Parkin function, the solution structure of the Parkin IBR domain was solved by using NMR spectroscopy. Folding of the IBR domain (residues M327-S378) was found to be zinc dependent, and the structure reveals the domain forms a unique pair scissor-like and GAG knuckle-like zinc-binding sites, different from other zinc-binding motifs such as the RING, LIM, PHD, or B-box motifs. The N terminus of the IBR domain, residues E307-E322, is unstructured. The disease causing mutation T351P causes global unfolding, whereas the mutation R334C causes some structural rearrangement of the domain. In contrast, the protein containing the mutation G328E appears to be properly folded. The structure of the Parkin IBR domain, in combination with mutational data, allows a model to be proposed where the IBR domain facilitates a close arrangement of the adjacent RING1 and RING2 domains to facilitate protein interactions and subsequent ubiquitination.ubiquitination ͉ zinc-binding ͉ NMR spectroscopy ͉ protein folding ͉ protein interactions P arkinson's disease (PD) is a common neurodegenerative disease characterized by damage to the dopaminergic neurons of the substantia nigra of the midbrain manifesting itself with symptoms such as tremors, rigidity, and bradykinesia (1, 2). Autosomal recessive juvenile PD (ARJP) is an early-onset (Ͻ40 years of age) form of the disease that is caused by hereditary factors including mutations in the genes DJ-1, PINK1, and in about half of the cases, parkin. The protein Parkin has been identified as an E3 ubiquitin-protein ligase of the ubiquitin-proteosome system that is required to maintain cellular protein quality control by removing misfolded or damaged proteins (3, 4). Ubiquitin mediated proteolysis occurs through a cascade of ubiquitin transfers from an E1 activating enzyme, to an E2 conjugating enzyme and finally in complex with an E3 ligase to the target substrate (5, 6). At least 40 different missense and deletion mutations in the parkin gene have been identified and correlated to dysfunction of the ubiquitination system, manifesting itself as ARJP due to the loss of the dopaminergic neurons (7).Parkin is a 465-residue protein comprising an N-terminal ubiquitin-like domain, a unique Parkin-specific domain in the central region, and two RING finger domains (RING1, RING2) separated by an in-between ring (IBR) or double ring linked domain near its C terminus. The cysteine and histidine rich RING-IBR-RING (RBR) domain architecture is highly conserved and found only in eukaryotes. To date, all characterized proteins containing the ...

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“…Full-length UbcH7 was cloned into pcDNA3-GFP to create UbcH7.pcDNA3 (Ardley et al 2001). The UbcH7 C89S mutant was generated from UbcH7.pcDNA3 to create C89SUbcH7.pcDNA3 using the QuikChange site-directed mutagenesis kit (Stratagene, Amsterdam, The Netherlands) according to the manufacturer's protocol (Ardley et al 2003).…”

Section: Plasmidsmentioning

confidence: 99%

UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation

Garside

Waters

Berry

et al. 2006

Journal of Endocrinology

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Unlike other nuclear receptors, transactivation by the glucocorticoid receptor (GR) is increased by the inhibition of the ubiquitin/proteasome pathway. Here, we demonstrate that the ubiquitin-conjugating enzyme (E2), UbcH7, physically interacts with the GR and, when overexpressed, reduces the ability of the receptor to upregulate gene expression. Chemical inhibition of the 26S proteasome abolished the downregulation effect of overexpressed UbcH7, suggesting a role for the 26S proteasome, and GR protein stability in mediating the UbcH7 effect. Furthermore, a UbcH7 dominant negative mutant (C89S), unable to transfer ubiquitin, failed to repress GR transactivation. Indeed, overexpression of the mutant UbcH7 was sufficient to augment GR transactivation to levels achieved using the proteasome inhibitor MG132, but there was no further induction when MG132 and the UbcH7 mutant were used together. Expression of the dominant negative UbcH7 abolished ligand-dependent downregulation of GR protein, suggesting that the UbcH7 effect was mediated by regulation of GR protein concentration. Taken together, these data show that UbcH7 is a key regulator of GR turnover and glucocorticoid sensitivity.

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Features of the Parkin/Ariadne-like Ubiquitin Ligase, HHARI, That Regulate Its Interaction with the Ubiquitin-conjugating Enzyme, UbcH7

Cited by 68 publications

References 46 publications

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson's disease

UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation

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