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

Hans, Friederike; Fiesel, Fabienne C.; Strong, Jennifer C.; Jäckel, Sandra; Rasse, Tobias M.; Geisler, Sven; Springer, Wolfdieter; Schulz, Jörg B.; Voigt, Aaron; Kahle, Philipp J.

doi:10.1074/jbc.m114.561704

Cited by 73 publications

(85 citation statements)

References 69 publications

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“…Extensive RBM45 pathology was observed in patients with C9ORF72 repeat expansions. RBM45 was subsequently found to bind and colocalize with the C-terminal fragment of TDP-43 implicated in ALS (11), consistent with a role for RBM45 in ALS pathobiology.…”

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confidence: 60%

“…The accumulation of TDP-43 and other RNA binding proteins in cytoplasmic stress granules may be a more generalized response to eliminate aggregated or mislocalized proteins, whereas RBM45 effectively binds and stabilizes KEAP1 when located at the cytoplasm or stress granules. In addition, RBM45 was recently identified as a TDP-43 binding partner by using a yeast two-hybrid system that used the C-terminal fragment of TDP-43 implicated in ALS (11), suggesting that the two proteins could be functioning as part of similar pathways in disease. More importantly, both RBM45 and TDP-43 have been shown to partially colocalize to cytoplasmic inclusions in motor neurons of ALS spinal cords (9,63).…”

Section: Discussionmentioning

confidence: 99%

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RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.A myotrophic lateral sclerosis (ALS) is a fatal idiopathic adultonset neurodegenerative disease characterized by a loss of motor neurons in the brain, brain stem, and spinal cord, with consequent atrophy of associated muscles (1, 2). Incidence rates are 1 to 3 cases per 100,000 individuals per year. Pathogenic mechanisms underlying the disease are not fully understood. Approximately 5 to 10% of all ALS cases are familial (3), with the remaining cases being termed sporadic, contributing to the clinical heterogeneity within the patient population. Nevertheless, typical hallmarks of ALS include neuronal atrophy, mitochondrial dysfunction, excitotoxicity, oxidative stress, and ubiquitinated cellular inclusions (4, 5). A growing number of genes with diverse functions have been implicated in the disease etiology. Mutations in a number of RNA binding proteins have been linked to ALS, including TAR DNA binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) (6). Mutations in these genes result in reduced levels in the nucleus and their accumulation in cytoplasmic ubiquitin-positive inclusions (7). Both TDP-43 and FUS possess prion-like domains and relocate to cytoplasmic stress granules under stress conditions, suggesting potential pathology commonalities (8). Genetic alterations in these and other RNA binding proteins link RNA metabolism to the pathobiology of ALS.Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10). RBM45 possesses three RNA recognition motifs (RRMs) as well as a C-terminal nuclear localization sequence (10). By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbia...

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confidence: 60%

Section: Discussionmentioning

confidence: 99%

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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“…Recently, the E3 ubiquitin ligase Parkin was proposed to ubiquitinate TDP-43, regulating its subcellular transport (Hebron et al, 2013). In D. melanogaster models, the ubiquitin-conjugating enzyme UBE2E3 promotes ubiquitination of TDP-43; in contrast, ubiquitin isopeptidase Y (UBPY) decreased TDP-43 ubiquitination (Hans et al, 2014). Furthermore, knockdown of UBPY promotes formation of insoluble TDP-43 aggregates and induced neurotoxicity in D. melanogaste r (Hans et al, 2014).…”

Section: Neurotoxicity Of Tdp-43/ Fusmentioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

Progress in Neurobiology

107

122

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Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

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“…As many lines of evidence show that TDP-43 ubiquitination provides a strong driving force for the formation of intracellular inclusion bodies in ALS or FTLD, we focused on this modification and investigated whether the ubiquitination of TDP-43 is necessary for the formation of subnuclear InSAC and the processing of IL-6 RNA. In particular, as the ubiquitin-conjugating enzyme UBE2E3 regulates TDP-43 ubiquitination 31 , we generated macrophages stably expressing UBE2E3 shRNA and examined TDP-43 ubiquitination in LPS-stimulated macrophages. We clearly observed that UBE2E3 depletion reduced TDP-43 ubiquitination in the presence of LPS (Fig.…”

Section: Nature Communications | Doimentioning

confidence: 99%

Identification of a subnuclear body involved in sequence-specific cytokine RNA processing

Lee

et al. 2015

Nat Commun

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Processing of interleukin RNAs must be tightly controlled during the immune response. Here we report that a subnuclear body called the interleukin-6 and -10 splicing activating compartment (InSAC) is a nuclear site of cytokine RNA production and stability. Tat-activating regulatory DNA-binding protein-43 (TDP-43) acts as an InSAC scaffold that selectively associates with IL-6 and IL-10 RNAs in a sequence-specific manner. TDP-43 also recruits key spliceosomal components from Cajal bodies. LPS induces posttranslational modifications of TDP-43; in particular, TDP-43 ubiquitination provides a driving force for InSAC formation. As a consequence, in vivo depletion of TDP-43 leads to a dramatic reduction in the RNA processing and the protein levels of IL-6 in serum. Collectively, our findings highlight the importance of TDP-43-mediated InSAC biogenesis in immune regulation.

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

Cited by 73 publications

References 69 publications

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

TDP-43/FUS in motor neuron disease: Complexity and challenges

Identification of a subnuclear body involved in sequence-specific cytokine RNA processing

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