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

Bakkar, Nadine; Kousari, Arianna; Kovalik, Tina; Li, Yang; Bowser, Robert

doi:10.1128/mcb.00087-15

Cited by 23 publications

(17 citation statements)

References 62 publications

(80 reference statements)

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“…This localization was consistent with that of endogenous Drb1 protein reported previously in human neuronal cells (22,24) or T7-tagged Drb1 (Fig. 1B).…”

Section: Resultssupporting

confidence: 92%

“…Using a yeast two-hybrid system, it was determined that the carboxyl-terminal region of TDP-43 interacts with Drb1 (23). Drb1 is also redistributed from the nucleus to the cytoplasm by oxidative stresses such as H 2 O 2 and paraquat and modulates the antioxidant response via cytoplasmic interaction with Kelch-like ECH-associated protein 1 (KEAP1), an inhibitor of the antioxidant response transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) (24). Despite these findings in relation to ALS pathology, the mechanism underlying the formation of Drb1 cytoplasmic aggregation remains unclear.…”

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confidence: 99%

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Developmentally Regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-Cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates

Mashiko

Sakashita

Kasashima

et al. 2016

Journal of Biological Chemistry

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Cytoplasmic protein aggregates are one of the pathological hallmarks of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Several RNA-binding proteins have been identified as components of inclusion bodies. Developmentally regulated RNA-binding protein 1 (Drb1)/RNA-binding motif protein 45 is an RNA-binding protein that was recently described as a component in ALS-and FTLD-related inclusion bodies. However, the molecular mechanism underlying cytoplasmic Drb1 aggregation remains unclear. Here, using an in vitro cellular model, we demonstrated that Drb1 co-localizes with cytoplasmic aggregates mediated by TAR DNA-binding protein 43, a major component of ALS and FTLD-related inclusion bodies. We also defined the domains involved in the subcellular localization of Drb1 to clarify the role of Drb1 in the formation of cytoplasmic aggregates in ALS and FTLD. Drb1 predominantly localized in the nucleus via a classical nuclear localization signal in its carboxyl terminus and is a shuttling protein between the nucleus and cytoplasm. Furthermore, we identify a double leucine motif serving as a nuclear export signal. The Drb1 mutant, presenting mutations in both nuclear localization signal and nuclear export signal, is prone to aggregate in the cytoplasm. The mutant Drb1-induced cytoplasmic aggregates not only recruit TAR DNA-binding protein 43 but also decrease the mitochondrial membrane potential. Taken together, these results indicate that perturbation of Drb1 nuclearcytoplasmic trafficking induces toxic cytoplasmic aggregates, suggesting that mislocalization of Drb1 is involved in the cause of cytotoxicity in neuronal cells. ALS,2 one of the most devastating and untreatable neurodegenerative diseases, affects motor neurons selectively with relentless progression and causes respiratory failure within 2-5 years from onset. Although 5-10% of ALS cases are familial, ϳ90% of cases are sporadic with unknown etiology (1). In contrast, frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases that affect frontal and temporal cortices with characteristic cognitive defects such as personality and behavioral changes as well as progressive deterioration of language skills (2). A subgroup of patients presents overlapped clinical characteristics of ALS and FTLD. Cytoplasmic inclusion bodies in neuronal cells are a common pathological hallmark in ALS and FTLD, implying that a common etiological pathway exists in ALS and FTLD pathogenesis (1, 3). TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein, was the first protein identified in cytoplasmic inclusion bodies in most sporadic ALS and several FTLD cases (4, 5). Since then, other RNA-binding proteins, such as fused in sarcoma/translated in liposarcoma (FUS/TLS), and heterogeneous nuclear ribonucleoproteins were also identified as components of cytoplasmic inclusion bodies. Because disease-associated mutations in the TDP-43 or FUS/TLS gene were identified in several familial ALS and F...

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“…This localization was consistent with that of endogenous Drb1 protein reported previously in human neuronal cells (22,24) or T7-tagged Drb1 (Fig. 1B).…”

Section: Resultssupporting

confidence: 92%

mentioning

confidence: 99%

Developmentally Regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-Cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates

Mashiko

Sakashita

Kasashima

et al. 2016

Journal of Biological Chemistry

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“…Intriguingly, proteins that associate with KEAP1 impact KEAP1 stability without disrupting the KEAP1-NRF2 binding interface. For example, RNA-binding motif 45 (RBM45) is known to bind and stabilize KEAP1 protein in motor neurons with amyotrophic lateral sclerosis (102). Although changes in RBM45 expression in tumors have not been extensively studied, recent proteomic studies examining reactive cysteines in KEAP1-mutant non-small cell lung cancer cell lines revealed protein-protein interactions between the cysteine-reactive nuclear factor receptor subfamily 0 group B member 1 (NR0B1) and RBM45 (103).…”

Section: V334 S363mentioning

confidence: 99%

NRF2 Activation in Cancer: From DNA to Protein

et al. 2019

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The Cancer Genome Atlas catalogued alterations in the Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across 226 studies, with significant enrichment in lung and upper airway cancers. These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming. Almost universally, NRF2 activity strongly associates with poor patient prognosis and chemo-and radioresistance. Yet to date, FDA-approved drugs targeting NRF2 activity in cancer have not been realized.Here, we review various mechanisms that contribute to NRF2 activation in cancer, organized around the central dogma of molecular biology (i) at the DNA level with genomic and epigenetic alterations, (ii) at the RNA level including differential mRNA splicing and stability, and (iii) at the protein level comprising altered posttranslational modifications and protein-protein interactions. Ultimately, defining and understanding the mechanisms responsible for NRF2 activation in cancer may lead to novel targets for therapeutic intervention.

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“…Recent studies identified co-localization of TDP-43 and RNA-binding motif-45 (RBM45) inclusions and their RNA-dependent association in motor neurons of some cases of ALS (Collins et al, 2012; Mladinic et al, 2010). Like TDP-43, RBM-45 is mainly nuclear, but migrates to cytoplasm and co-localizes in SGs to associate with Kelch-like ECH-Associated protein 1, a component of anti-oxidant machinery (Bakkar et al, 2015). Furthermore, TDP-43 co-localizes in cytoplasmic inclusions with Poly-A binding protein - 1 (PABP-1); a stress granules marker (McGurk et al, 2014).…”

Section: Introductionmentioning

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

Cited by 23 publications

References 62 publications

Developmentally Regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-Cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates

Developmentally Regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-Cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates

NRF2 Activation in Cancer: From DNA to Protein

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

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