LUC7L3/CROP inhibits replication of hepatitis B virus via suppressing enhancer II/basal core promoter activity

Li, Yuan; Ito, Masahiko; Sun, Suofeng; Chida, Takeshi; Nakashima, Kenichiro; Suzuki, Tetsuro

doi:10.1038/srep36741

Cited by 25 publications

(20 citation statements)

References 42 publications

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“…6A). As expected, all three proteins localize to nuclear granules (30,45,46), where U1-70K shows strong colocalization with LUC7L3 and RBM25 ( Fig. 7A).…”

Section: Bad Domains In Luc7l3 and Rbm25 Are Necessary For Reciprocalsupporting

confidence: 83%

RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease

Bishof

Dammer

Duong

et al. 2018

Journal of Biological Chemistry

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The U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other RNA-binding proteins (RBPs) are mislocalized to cytoplasmic neurofibrillary Tau aggregates in Alzheimer's disease (AD), yet the co-aggregation mechanisms are incompletely understood. U1-70K harbors two disordered low-complexity domains (LC1 and LC2) that are necessary for aggregation in AD brain extracts. The LC1 domain contains highly repetitive basic (Arg/Lys) and acidic (Asp/Glu) residues, referred to as a basic-acidic dipeptide (BAD) domain. We report here that this domain shares many of the properties of the Gln/Asn-rich LC domains in RBPs that also aggregate in neurodegenerative disease. These properties included self-assembly into oligomers and localization to nuclear granules. Co-immunoprecipitations of recombinant U1-70K and deletions lacking the LC domain(s) followed by quantitative proteomic analyses were used to resolve functional classes of U1-70K-interacting proteins that depend on the BAD domain for their interaction. Within this interaction network, we identified a class of RBPs with BAD domains nearly identical to that found in U1-70K. Two members of this class, LUC7L3 and RBM25, required their respective BAD domains for reciprocal interactions with U1-70K and nuclear granule localization. Strikingly, a significant proportion of RBPs with BAD domains had elevated insolubility in the AD brain proteome. Furthermore, we show that the BAD domain of U1-70K can interact with Tau from AD brains but not from other tauopathies. These findings highlight a mechanistic role for BAD domains in stabilizing RBP interactions and in potentially mediating co-aggregation with the pathological AD-specific Tau isoforms.

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“…6A). As expected, all three proteins localize to nuclear granules (30,45,46), where U1-70K shows strong colocalization with LUC7L3 and RBM25 ( Fig. 7A).…”

Section: Bad Domains In Luc7l3 and Rbm25 Are Necessary For Reciprocalsupporting

confidence: 83%

RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease

Bishof

Dammer

Duong

et al. 2018

Journal of Biological Chemistry

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“…Both RBM25 and LUC7L3 have mixed charge domains analogous to the LC1 domain of U1-70K with similarity E-values of 5.5E-27 and 1.8E-26, respectively, and amino acid overlap of 55.1% and 44.2%, respectively (Fig 6A). As expected, all three proteins were observed in nuclear granules (30,47,48), where U1-70K showed strong co-localization with LUC7L3 and RBM25 ( Fig. 7A).…”

Section: Mixed Charge Domains In Luc7l3 and Rbm25 Are Necessary For Rsupporting

confidence: 83%

RNA-binding proteins with mixed charge domains self-assemble and aggregate in Alzheimer’s Disease

Bishof

Dammer

Duong

et al. 2018

Preprint

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U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other RNA binding proteins (RBPs) are mislocalized to cytoplasmic neurofibrillary Tau aggregates in Alzheimer's disease (AD), yet understanding of the mechanisms that cause their aggregation is limited. Many RBPs that aggregate in neurodegenerative diseases self-assemble into RNA granules through intrinsically disordered low complexity (LC) domains. We report here that a LC domain within U1-70K of mixed charge, containing highly repetitive complementary repeats of basic (R/K) and acidic (D/E) residues, shares many of the same properties of the Q/N-rich LC domains found in the RBPs TDP-43 and FUS. These properties include the ability to self-assemble into oligomers, and to form nuclear granules. To analyze the functional roles of the U1-70K LC domains, we performed coimmunoprecipitation and quantitative mass spectrometry analysis of recombinant U1-70K and deletions lacking the C-terminal LC domain(s). A network-driven approach resolved functional classes of U1-70K interacting proteins that showed dependency on the U1-70K LC domain(s) for their interaction. This included structurally similar RBPs, such as LUC7L3 and RBM25, which require their respective mixed charge domains for reciprocal interactions with U1-70K and for participation in nuclear RNA granules. Strikingly, a significant proportion of RBPs with mixed charge domains have elevated insolubility in AD brain proteome compared to controls. Furthermore, we show that the mixed charge LC domain of U1-70K can interact with Tau from AD brain. These findings highlight mechanisms for mixed charge domains in stabilizing RBP interactions and in potentially mediating coaggregation with pathological Tau isoforms in AD. INTRODUCTION The molecular processes that contribute to neurodegenerative diseases are not well understood. Recent observations suggest that numerous neurodegenerative diseases are promoted by the accumulation of RNA-binding protein (RBP) aggregates (1-3). This includes Alzheimer's disease (AD), where pathological RNA-protein aggregates are often, but not exclusively, associated with Tau neurofibrillary . CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/243014 doi: bioRxiv preprint first posted online Jan. 4, 2018; Mixed Charge RNA binding proteins aggregate in AD 2 tangles in brain (4). For example, U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other core components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of AD (5-7). Furthermore, RNA-seq analysis from AD and control brains revealed a significant accumulation of unspliced pre-mRNA disease related transcripts in AD consistent with a loss of U1-spliceosome function (7,8). Currently, our knowledge of the specific mechanisms underlying U1-70K aggregation is limited. This has proved to be a barrier to developing cellular models that wou...

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“…LUC7L3—which has a strong sequence similarity with yeast U1 snRNP component Luc7p—has also been shown to participate in the cisplatin‐induced resistance of tumor cells . Another report suggests LUC7L3 protein binding to the cAMP‐responsive element, and a recent article claimed antiviral property for this splicing regulator . Relatively few data are available for SFRS18.…”

Section: Discussionmentioning

confidence: 99%

Analysis of psoriasis‐relevant gene expression and exon usage alterations after silencing of SR‐rich splicing regulators

Szlávicz

Oláh

Szabó

et al. 2018

Experimental Dermatology

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In our recent cDNA microarray experiment, three SR‐rich splicing factors—SFRS18, PPIG and LUC7L3—were shown to exert altered responsiveness upon T‐lymphokine stimulation of psoriatic non‐involved and healthy epidermis samples. We have also demonstrated that double silencing LUC7L3 and SFRS18 efficiently decreased production of the psoriasis‐associated EDA+ fibronectin isoform. These findings prompted the further investigation of signalling pathways affected by LUC7L3 and SFRS18. To detect gene expression and splicing pattern alterations upon double silencing of LUC7L3 and SFRS18 in an HPV‐immortalised keratinocyte cell culture, paired‐end RNA sequencing was carried out. Marked changes in exon usage were revealed, in contrast to the modest alterations detected in gene expression, providing a closer delineation of the potential targets of the examined splicing factors. The most prominent gene expression change was detected for IFI6, an interferon‐inducible gene highly expressed in psoriasis. Interacting partners of IFI6 and certain psoriasis‐associated transcripts also exhibited significantly increased expression upon silencing. In addition to elevated abundance of the EDA+ fibronectin interactor ITGA5, we confirmed decreased EDA domain inclusion, which agrees well with our prior experimental data. Furthermore, differential exon usage was established for the transcription element CREB1, along with HERC6 and CUL1, which are implicated in ubiquitination. Although immortalised keratinocytes express low levels of TINCR, a long non‐coding RNA involved in terminal differentiation of keratinocytes, splicing alterations were successfully demonstrated for this RNA as well. We believe that the targeted investigation of mRNA maturation disturbances may help us gain deeper insight into the molecular pathogenesis of psoriasis.

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LUC7L3/CROP inhibits replication of hepatitis B virus via suppressing enhancer II/basal core promoter activity

Cited by 25 publications

References 42 publications

RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease

RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease

RNA-binding proteins with mixed charge domains self-assemble and aggregate in Alzheimer’s Disease

Analysis of psoriasis‐relevant gene expression and exon usage alterations after silencing of SR‐rich splicing regulators

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