Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli

Emerging evidence suggests that extracellular vesicle (EV)–containing miRNAs mediate intercellular communications in response to noxious stimuli. It remains unclear how a cell selectively sorts the cellular miRNAs into EVs. We report that caveolin-1 (cav-1) is essential for sorting of selected miRNAs into microvesicles (MVs), a main type of EVs generated by outward budding of the plasma membrane. We found that cav-1 tyrosine 14 (Y14)–phosphorylation leads to interactions between cav-1 and hnRNPA2B1, an RNA-binding protein. The cav-1/hnRNPA2B1 complex subsequently traffics together into MVs. Oxidative stress induces O-GlcNAcylation of hnRNPA2B1, resulting in a robustly altered hnRNPA2B1-bound miRNA repertoire. Notably, cav-1 pY14 also promotes hnRNPA2B1 O-GlcNAcylation. Functionally, macrophages serve as the principal recipient of epithelial MVs in the lung. MV-containing cav-1/hnRNPA2B1 complex-bound miR-17/93 activate tissue macrophages. Collectively, cav-1 is the first identified membranous protein that directly guides RNA-binding protein into EVs. Our work delineates a novel mechanism by which oxidative stress compels epithelial cells to package and secrete specific miRNAs and elicits an innate immune response.

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The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

Antioxidants ◽

10.3390/antiox10040552 ◽

2021 ◽

Vol 10 (4) ◽

pp. 552

Author(s):

Jasmine Harley ◽

Benjamin E. Clarke ◽

Rickie Patani

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Mitochondrial Dysfunction ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Therapeutic Strategies ◽

Lateral Sclerosis

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

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

Molecular and Cellular Biology ◽

10.1128/mcb.00087-15 ◽

2015 ◽

Vol 35 (14) ◽

pp. 2385-2399 ◽

Cited By ~ 12

Author(s):

Nadine Bakkar ◽

Arianna Kousari ◽

Tina Kovalik ◽

Yang Li ◽

Robert Bowser

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Antioxidant Response ◽

Cytoplasmic Inclusions ◽

Lateral Sclerosis

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 recapitulatedin vitroin 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.

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RNA-binding protein Csx1 is phosphorylated by LAMMER kinase, Lkh1, in response to oxidative stress inSchizosaccharomyces pombe

FEBS Letters ◽

10.1016/j.febslet.2007.06.053 ◽

2007 ◽

Vol 581 (18) ◽

pp. 3473-3478 ◽

Cited By ~ 13

Author(s):

Won-Hwa Kang ◽

Yoon-Dong Park ◽

Ji-Sook Hwang ◽

Hee-Moon Park

Keyword(s):

Oxidative Stress ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein

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733 - The RNA Binding Protein HUR Regulates Extracellular Vesicle Secretion in Colorectal Cancer

Gastroenterology ◽

10.1016/s0016-5085(18)30923-5 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-151-S-152

Author(s):

Ranjan Preet ◽

Wei-Ting Hung ◽

Vikalp Vishwakarma ◽

Lane Christenson ◽

Dan A. Dixon

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Extracellular Vesicle ◽

Vesicle Secretion

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The RNA binding protein HuR regulates the senescence-associated secretory phenotype under conditions of oxidative stress

10.1183/13993003.congress-2019.pa2374 ◽

2019 ◽

Cited By ~ 1

Author(s):

Shyreen Hassibi ◽

Jonathan Baker ◽

Louise Donnelly ◽

Peter Barnes

Keyword(s):

Oxidative Stress ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Secretory Phenotype

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A Novel RNA-Binding Protein, Ossa/C9orf10, Regulates Activity of Src Kinases To Protect Cells from Oxidative Stress-Induced Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.01035-08 ◽

2008 ◽

Vol 29 (2) ◽

pp. 402-413 ◽

Cited By ~ 21

Author(s):

Masamitsu Tanaka ◽

Kazuki Sasaki ◽

Reiko Kamata ◽

Yukari Hoshino ◽

Kazuyoshi Yanagihara ◽

...

Keyword(s):

Oxidative Stress ◽

Tumor Cells ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Pi3 Kinase ◽

Scaffolding Protein ◽

Functional Protein ◽

Uncharacterized Protein ◽

Induced Apoptosis

ABSTRACT During the process of tumor progression and clinical treatments, tumor cells are exposed to oxidative stress. Tumor cells are frequently resistant to such stress by producing antiapoptotic signaling, including activation of Src family kinases (SFKs), although the molecular mechanism is not clear. In an attempt to identify the SFK-binding proteins selectively phosphorylated in gastric scirrhous carcinoma, we identified an uncharacterized protein, C9orf10. Here we report that C9orf10 (designated Ossa for oxidative stress-associated Src activator) is a novel RNA-binding protein that guards cancer cells from oxidative stress-induced apoptosis by activation of SFKs. Exposure to oxidative stress such as UV irradiation induces the association of Ossa/C9orf10 with regulatory domains of SFKs, which activates these kinases and causes marked tyrosine phosphorylation of C9orf10 in turn. Tyrosine-phosphorylated Ossa recruits p85 subunits of phosphatidylinositol 3-kinase (PI3-kinase) and behaves as a scaffolding protein for PI3-kinase and SFKs, which activates the Akt-mediated antiapoptotic pathway. On the other hand, the carboxyl terminus of Ossa has a distinct function that directly binds RNAs such as insulin-like growth factor II (IGF-II) mRNA and promotes the extracellular secretion of IGF-II. Our findings indicate that Ossa is a dual-functional protein and might be a novel therapeutic target which modulates the sensitivity of tumors to oxidative stress.

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