Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron

Han, Ke-Jun; Foster, Daniel G.; Zhang, Nanyan; Kavdia, Kanisha; Dzieciątkowska, Monika; Sclafani, Robert A.; Hansen, Kirk C.; Peng, Junmin; Liu, Changwei

doi:10.1074/jbc.m112.372318

Cited by 55 publications

(57 citation statements)

References 77 publications

(82 reference statements)

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“…DUB inhibitors can also be used to augment protein ubiquitylation and increase substrate detection; however, proteasome impairment was found to be a more effective approach for increasing levels of ubiquitylation sites (29,30 pharmacological DUB inhibition results in the widespread accumulation of substrates, similar to proteasome inhibition, which is contrary to what might be predicted upon DUB inhibition. This is because many studies have reported a decrease in substrate abundance upon RNAi-based knockdown of individual DUBs (33)(34)(35)(36)(37). This discrepancy may be explained by the fact that although knockdown results in protein depletion, an inhibitor inactivates the enzyme, possibly allowing for sustained substrate binding and possible sequestration.…”

mentioning

confidence: 72%

Using the Ubiquitin-modified Proteome to Monitor Protein Homeostasis Function

Carrano

Bennett

2013

Molecular & Cellular Proteomics

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The ubiquitin system is essential for the maintenance of proper protein homeostasis function across eukaryotic species. Although the general enzymatic architecture for adding and removing ubiquitin from substrates is well defined, methods for the comprehensive investigation of cellular ubiquitylation targets have just started to emerge. Recent advances in ubiquitin-modified peptide enrichment have greatly increased the number of identified endogenous ubiquitylation targets, as well as the number of sites of ubiquitin attachment within these substrates. Herein we evaluate current strategies using mass-spectrometry-based proteomics to characterize ubiquitin and ubiquitin-like modifications. Using existing data, we describe the characteristics of the ubiquitin-modified proteome and discuss strategies for the biological interpretation of existing and future ubiquitin-based proteomic studies. Molecular & Cellular

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mentioning

confidence: 72%

Using the Ubiquitin-modified Proteome to Monitor Protein Homeostasis Function

Carrano

Bennett

2013

Molecular & Cellular Proteomics

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“…Previously, USP9X was found to interact with another Tudor domain-containing protein, survival motor neuron (SMN) protein [50, 51]. Mutation/deletion of SMN-coding gene, SMN1 , accounts for 95% of spinal muscular atrophy (SMA), an autosomal recessive disorder that results in degeneration of α-motor neurons in the spinal cord [52].…”

Section: Discussionmentioning

confidence: 99%

Arginine methylation of USP9X promotes its interaction with TDRD3 and its anti-apoptotic activities in breast cancer cells

Narayanan

Wang

et al. 2017

Cell Discov

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The Tudor domain-containing proteins are characterized by their specific interactions with methylated protein motifs, including methyl-arginines and methyl-lysines. The Tudor domain-containing protein 3 (TDRD3) is one of the major methyl-arginine effector molecules that recognizes methylated arginine residues on histones and the C-terminal domain of RNA polymerase II, and activates transcription. However, majority of the cellular TDRD3 localizes to the cytoplasm and its functions there are still elusive. Here, we have identified ubiquitin-specific protease 9 X-linked (USP9X) as a TDRD3-interacting protein by GST (glutathione S-transferase) pull-down and co-immunoprecipitation. Detailed characterization suggests that the interaction between TDRD3 and USP9X is mediated through the Tudor domain of TDRD3 and the arginine methylation of USP9X. This interaction plays a critical role in TDRD3 protein stability, as knockdown of USP9X expression leads to increased TDRD3 ubiquitination. We also found that USP9X co-localizes with TDRD3 in cytoplasmic stress granules and this localization is diminished in Tdrd3-null mouse embryonic fibroblast cells, suggesting that TDRD3 is essential for USP9X stress granule localization. Furthermore, we found that one of the USP9X de-ubiquitination targets, myeloid cell leukemia protein 1, is regulated by TDRD3, indicating that TDRD3 potentially regulates USP9X de-ubiquitinase activity. Finally, we show that knockdown of TDRD3 expression sensitizes breast cancer cells to chemotherapeutic drug-induced apoptosis, likely due to its regulation of USP9X. This study provides a novel candidate strategy for targeting apoptosis pathways in cancer therapy.

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“…We previously reported that the E3 ubiquitin-protein ligase mind bomb-1 (Mib1) ubiquitinates SMN, targeting it for degradation (20). In addition Usp9x (also known (21). Usp9x/FAM also interacts with Mib1 (22), suggesting that they act together to regulate SMN protein levels.…”

Section: Ml372 Is Brain Penetrant and Has A Reasonable Exposure And Hmentioning

confidence: 99%

ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

Abera¹,

Xiao²,

Nofziger³

et al. 2016

JCI Insight

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Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron

Cited by 55 publications

References 77 publications

Using the Ubiquitin-modified Proteome to Monitor Protein Homeostasis Function

Using the Ubiquitin-modified Proteome to Monitor Protein Homeostasis Function

Arginine methylation of USP9X promotes its interaction with TDRD3 and its anti-apoptotic activities in breast cancer cells

ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

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