scholarly journals Phosphorylation and nuclear transit modulate the balance between normal function and terminal aggregation of the yeast RNA-binding protein Ssd1

2017 ◽  
Vol 28 (22) ◽  
pp. 3057-3069 ◽  
Author(s):  
Cornelia Kurischko ◽  
James R. Broach
Keyword(s):  
Rna Polymerase Ii ◽  
Nuclear Export ◽  
Rna Binding ◽  
Binding Protein ◽  
Neurological Diseases ◽  
Rna Binding Protein ◽  
Normal Function ◽  
Nuclear Localization Sequence ◽  
P Bodies ◽  
Localization Sequence

Yeast Ssd1 is an RNA-binding protein that shuttles between the nucleus and cytoplasm. Ssd1 interacts with its target mRNAs initially during transcription by binding through its N-terminal prion-like domain (PLD) to the C-terminal domain of RNA polymerase II. Ssd1 subsequently targets mRNAs acquired in the nucleus either to daughter cells for translation or to stress granules (SGs) and P-bodies (PBs) for mRNA storage or decay. Here we show that PB components assist in the nuclear export of Ssd1and subsequent targeting of Ssd1 to PB sites in the cytoplasm. In the absence of import into the nucleus, Ssd1 fails to associate with PBs in the cytoplasm but rather is targeted to cytosolic insoluble protein deposits (IPODs). The association of Ssd1 either with IPOD sites or with PB/SG requires the PLD, whose activity is differentially regulated by the Ndr/LATS family kinase, Cbk1: phosphorylation suppresses PB/SG association but enhances IPOD formation. This regulation likely accrues from a phosphorylation-sensitive nuclear localization sequence located in the PLD. The results presented here may inform our understanding of aggregate formation by RBP in certain neurological diseases.

scholarly journals Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

2020 ◽  
pp. 0271678X2091686 ◽  
Author(s):  
Fang Shen ◽  
Xiang Xu ◽  
Zhengquan Yu ◽  
Haiying Li ◽  
Haitao Shen ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Protein Level ◽  
Rna Binding ◽  
Neuronal Degeneration ◽  
Binding Protein ◽  
Neurological Diseases ◽  
Rna Binding Protein ◽  
Micro Rna ◽  
Secondary Brain Injury

RNA-binding protein fox-1 homolog 1 (Rbfox-1), an RNA-binding protein in neurons, is thought to be associated with many neurological diseases. To date, the mechanism on which Rbfox-1 worsens secondary cell death in ICH remains poorly understood. In this study, we aimed to explore the role of Rbfox-1 in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and to identify its underlying mechanisms. We found that the expression of Rbfox-1 in neurons was significantly increased after ICH, which was accompanied by increases in the binding of Rbfox-1 to Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) mRNA and the protein level of CaMKIIα. In addition, when exposed to exogenous upregulation or downregulation of Rbfox-1, the protein level of CaMKIIα showed a concomitant trend in brain tissue, which further suggested that CaMKIIα is a downstream-target protein of Rbfox-1. The upregulation of both proteins caused intracellular-Ca2+ overload and neuronal degeneration, which exacerbated brain damage. Furthermore, we found that Rbfox-1 promoted the expression of CaMKIIα via blocking the binding of micro-RNA-124 to CaMKIIα mRNA. Thus, Rbfox-1 is expected to be a promising therapeutic target for SBI after ICH.

Fragile X family members have important and non-overlapping functions

2011 ◽  
Vol 2 (5) ◽  
pp. 343-352 ◽  
Author(s):  
Claudia Winograd ◽  
Stephanie Ceman
Keyword(s):  
Nuclear Export ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Family Members ◽  
Nuclear Localization Sequence ◽  
Interaction Domain ◽  
Protein Protein Interaction ◽  
Localization Sequence ◽  
Protein Functional Domains

AbstractThe fragile X family of genes encodes a small family of RNA binding proteins including FMRP, FXR1P and FXR2P that were identified in the 1990s. All three members are encoded by 17 exons and show alternative splicing at the 3′ ends of their respective transcripts. They share significant homology in the protein functional domains, including the Tudor domains, the nuclear localization sequence, a protein-protein interaction domain, the KH1 and KH2 domains and the nuclear export sequence. Fragile X family members are found throughout the animal kingdom, although all three members are not consistently present in species outside of mammals: only two family members are present in the avian species examined, Gallus gallus and Taeniopygia guttata, and in the frog Xenopus tropicalis. Although present in many tissues, the functions of the fragile X family members differ, which are particularly evident in knockout studies performed in animals. The fragile X family members play roles in normal neuronal function and in the case of FXR1, in muscle function.

scholarly journals KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral multiplication by interaction with Ago2 and GW182

2019 ◽  
Vol 47 (17) ◽  
pp. 9368-9385 ◽  
Author(s):  
Nishi R Sharma ◽  
Vladimir Majerciak ◽  
Michael J Kruhlak ◽  
Lulu Yu ◽  
Jeong Gu Kang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Time Lapse ◽  
Processing Bodies ◽  
P Bodies ◽  
Rna Granules ◽  
Inhibitory Function ◽  
Invasion Mechanisms ◽  
Initial Stage

Abstract Cellular non-membranous RNA-granules, P-bodies (RNA processing bodies, PB) and stress granules (SG), are important components of the innate immune response to virus invasion. Mechanisms governing how a virus modulates PB formation remain elusive. Here, we report the important roles of GW182 and DDX6, but not Dicer, Ago2 and DCP1A, in PB formation, and that Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic infection reduces PB formation through several specific interactions with viral RNA-binding protein ORF57. The wild-type ORF57, but not its N-terminal dysfunctional mutant, inhibits PB formation by interacting with the N-terminal GW-domain of GW182 and the N-terminal domain of Ago2, two major components of PB. KSHV ORF57 also induces nuclear Ago2 speckles. Homologous HSV-1 ICP27, but not EBV EB2, shares this conserved inhibitory function with KSHV ORF57. By using time-lapse confocal microscopy of HeLa cells co-expressing GFP-tagged GW182, we demonstrated that viral ORF57 inhibits primarily the scaffolding of GW182 at the initial stage of PB formation. Consistently, KSHV-infected iSLK/Bac16 cells with reduced GW182 expression produced far fewer PB and SG, but 100-fold higher titer of infectious KSHV virions when compared to cells with normal GW182 expression. Altogether, our data provide the first evidence that a DNA virus evades host innate immunity by encoding an RNA-binding protein that promotes its replication by blocking PB formation.

scholarly journals The RNA-binding protein FMRP facilitates the nuclear export of N6-methyladenosine–containing mRNAs

2019 ◽  
Vol 294 (52) ◽  
pp. 19889-19895 ◽  
Author(s):  
Phillip J. Hsu ◽  
Hailing Shi ◽  
Allen C. Zhu ◽  
Zhike Lu ◽  
Nimrod Miller ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein

scholarly journals The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing

2012 ◽  
Vol 196 (6) ◽  
pp. 699-712 ◽  
Author(s):  
Aymeric Ravel-Chapuis ◽  
Guy Bélanger ◽  
Ramesh S. Yadava ◽  
Mani S. Mahadevan ◽  
Luc DesGroseillers ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Alternative Splicing ◽  
Nuclear Export ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Splicing Regulation ◽  
Ribonucleic Acids ◽  
Dystrophia Myotonica Protein Kinase

In myotonic dystrophy type 1 (DM1), dystrophia myotonica protein kinase messenger ribonucleic acids (RNAs; mRNAs) with expanded CUG repeats (CUGexp) aggregate in the nucleus and become toxic to cells by sequestering and/or misregulating RNA-binding proteins, resulting in aberrant alternative splicing. In this paper, we find that the RNA-binding protein Staufen1 is markedly and specifically increased in skeletal muscle from DM1 mouse models and patients. We show that Staufen1 interacts with mutant CUGexp mRNAs and promotes their nuclear export and translation. This effect is critically dependent on the third double-stranded RNA–binding domain of Staufen1 and shuttling of Staufen1 into the nucleus via its nuclear localization signal. Moreover, we uncover a new role of Staufen1 in splicing regulation. Overexpression of Staufen1 rescues alternative splicing of two key pre-mRNAs known to be aberrantly spliced in DM1, suggesting its increased expression represents an adaptive response to the pathology. Altogether, our results unravel a novel function for Staufen1 in splicing regulation and indicate that it may positively modulate the complex DM1 phenotype, thereby revealing its potential as a therapeutic target.

scholarly journals The RNA-binding protein Sam68 is a multifunctional player in human cancer

2011 ◽  
Vol 18 (4) ◽  
pp. R91-R102 ◽  
Author(s):  
Pamela Bielli ◽  
Roberta Busà ◽  
Maria Paola Paronetto ◽  
Claudio Sette
Keyword(s):  
Nuclear Export ◽  
Rna Binding ◽  
Viral Infections ◽  
Human Cancer ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Mrna Translation ◽  
Endocrine Tumors ◽  
Recent Advancement ◽  
Kh Domain

Src associated in mitosis, of 68 kDa (Sam68) is a KH domain RNA-binding protein that belongs to the signal transduction and activation of RNA family. Although ubiquitously expressed, Sam68 plays very specialized roles in different cellular environments. In most cells, Sam68 resides in the nucleus and is involved in several steps of mRNA processing, from transcription, to alternative splicing, to nuclear export. In addition, Sam68 translocates to the cytoplasm upon cell stimulation, cell cycle transitions or viral infections, where it takes part to signaling complexes and associates with the mRNA translation machinery. Recent evidence has linked Sam68 function to the onset and progression of endocrine tumors, such as prostate and breast carcinomas. Notably, all the biochemical activities reported for Sam68 seem to be implicated in carcinogenesis. Herein, we review the recent advancement in the knowledge of Sam68 function and regulation and discuss it in the frame of its participation to neoplastic transformation and tumor progression.

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