Parkin Ubiquitinates Tar-DNA Binding Protein-43 (TDP-43) and Promotes Its Cytosolic Accumulation via Interaction with Histone Deacetylase 6 (HDAC6)

Hebron, Michaeline; Lonskaya, Irina; Sharpe, Kaydee; Weerasinghe, Puwakdandawe P.K.; Algarzae, Norah K.; Shekoyan, Ashot R.; Moussa, Charbel

doi:10.1074/jbc.m112.419945

Cited by 114 publications

(145 citation statements)

References 79 publications

(95 reference statements)

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“…The cognate ubiquitin ligase(s) of the UBE2E class of ubiquitination-promoting enzymes remains to be shown. One other candidate ubiquitin ligase for TDP-43 was recently reported, namely parkin (17). Parkin and UBE2E2 (UbcH8) were shown to interact (56,57), and for the polycomb protein RNF2 (RING1b), UBE2E1 (UbcH6) promoted histone H2A monoubiquitination (58).…”

Section: Discussionmentioning

confidence: 99%

“…In transfected cells, optimized conditions for co-immunoprecipitations between TDP-43 and UBE2E3 might argue for the requirement for a complexstabilizing E3. Parkin is a candidate for such a RING-type ubiquitin ligase for TDP-43 (17). Alternatively, UBE2E3 could be a novel example of a highly dynamic and/or weak physical interaction of an E2 directly interacting with its target protein, TDP-43.…”

Section: Discussionmentioning

confidence: 99%

“…As for TDP-43 degradation, controversial reports in the literature point to proteasomal breakdown (7)(8)(9)(10), autophagy (11,12), or both (13)(14)(15)(16). In a recent report, the ubiquitin ligase parkin was described to ubiquitinate TDP-43 in a complex manner, regulating subcellular TDP-43 transport (17).…”

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confidence: 99%

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UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination

Hans

Fiesel²,

Strong³

et al. 2014

Journal of Biological Chemistry

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Background: Ubiquitin-modified TDP-43 protein aggregates characterize common neurodegenerative diseases. Results: UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y (UBPY) are functional interactors of TDP-43 in cell culture and fly models. Conclusion: Specific regulators of TDP-43 ubiquitination influence its aggregation and neurotoxic properties. Significance: UBE2E and UBPY enzymes may modulate the course of TDP-43 diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination

Hans

Fiesel²,

Strong³

et al. 2014

Journal of Biological Chemistry

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“…In a pilot study, researchers delivered parkin genes to neurons which slowed down ALS pathologies linked to TDP-43 [36] . In another animal model, increased expression of UPF1, the master regulator of a nonsensemediated decay pathway, can significantly protect mammalian motor neurons from TDP-43 mediated toxicity.…”

Section: Targeting Tdp-43 As a Potential Treatment For Alsmentioning

confidence: 99%

The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

Dong¹,

Chen²

2018

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Deposition of intracellular ubiquitin inclusion in motor neurons is one of the leading pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). The transactive response DNA binding protein-43 (TDP-43) is the main component of intracellular ubiquitin inclusion bodies in pathological deposits. TDP-43 is mainly distributed in the nucleus of neurons, and participates in nuclear RNA transcription, alternative splicing and mRNA stability regulation. The tardbp , as a coding gene, provides instructions for making TDP-43. After post-translational modification, the pathological TDP-43 induces pathological deposition in cells and is associated with neurodegenerative diseases, which is similar to tau in Alzheimer's disease and alpha-synuclein in Parkinson's disease. The pathogenic tardbp mutation can affect the localization of reverse transcription in the cell. This review summarizes the mechanisms underlying the pathogenesis of ALS by ubiquitination of TDP-43 protein.

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“…Because HDAC6 had been implicated in protein degradation and clearance (35)(36)(37)(38)(39)(40)(41), we asked whether HDAC6 inhibition would affect the protein levels or the processing of GLI2/3. Treatment of NIH3T3 fibroblasts with the HDAC6 inhibitors ACY-1215 and CAY-10603 reduced the overall amount of full-length GLI2 protein as well as the amount of GLI3 activator (GLI3 A ) and repressor (GLI3 R ; Fig.…”

Section: Dichotomous Impact Of Hdac6 On Hh Signalingmentioning

confidence: 99%

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

Dhanyamraju

Holz

Finkernagel

et al. 2015

Molecular Cancer Therapeutics

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Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6 0 s impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened-and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma.

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Parkin Ubiquitinates Tar-DNA Binding Protein-43 (TDP-43) and Promotes Its Cytosolic Accumulation via Interaction with Histone Deacetylase 6 (HDAC6)

Cited by 114 publications

References 79 publications

UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination

UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination

The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

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