The effect of O -GlcNAcylation on hnRNP A1 translocation and interaction with transportin1

Roth, Shira; Khalaila, Isam

doi:10.1016/j.yexcr.2016.11.023

Cited by 23 publications

(25 citation statements)

References 48 publications

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“…Transportin 1 is a karyopherin which interacts with the nuclear localization sequence to target nuclear proteins to the nucleus. A report by Roth and Khalaila suggested that transportin 1 imports hnRNP A1 by interacting with its F-peptide (aa 301 to 318) in the M9 domain (9). Roth and Khalaila suggested that enhanced O-GlcNAcylation of hnRNP A1 increased its interaction with transportin 1, while enhanced phosphorylation reduced the interaction between the proteins (9).…”

Section: Discussionmentioning

confidence: 99%

“…Transportin 1 (or importin-␤2), which also belongs to the importin ␤ family, imports heterogeneous nuclear ribonucleoprotein (hnRNP) A1 (9). It functions in nuclear protein import as a nuclear transport receptor.…”

mentioning

confidence: 99%

“…2E), indicating that p17 interacts with both of these molecules (27) but not lamin A/C during nuclear import. Transportin 1 is reported to mediate nuclear import of hnRNP A1 (9). Reciprocal immunoprecipitation cell lysates were immunoprecipitated with the hnRNP A1 or Flag antibodies, and transportin 1 was detected by Western blotting assays ( Fig.…”

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confidence: 99%

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Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Chiu

Huang

Wang

et al. 2019

J Virol

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Avian reovirus (ARV) p17 protein continuously shuttles between the nucleus and the cytoplasm via transcription-dependent and chromosome region maintenance 1 (CRM1)-independent mechanisms. Nevertheless, whether cellular proteins modulate nucleocytoplasmic shuttling of p17 remains unknown. This is the first report that heterogeneous nuclear ribonucleoprotein (hnRNP) A1 serves as a carrier protein to modulate nucleocytoplasmic shuttling of p17. Both in vitro and in vivo studies indicated that direct interaction of p17 with hnRNP A1 maps within the amino terminus (amino acids [aa] 19 to 40) of p17 and the Gly-rich region of the C terminus of hnRNP A1. Furthermore, our results reveal that the formation of p17-hnRNP A1-transportin 1 carrier-cargo complex is required to modulate p17 nuclear import. Utilizing sequence and mutagenesis analyses, we have identified nuclear export signal (NES) 19 LSLRELAI 26 of p17. Mutations of these residues causes a nuclear retention of p17. In this work, we uncovered that the N-terminal 21 amino acids (aa 19 to 40) of p17 that comprise the NES can modulate both p17 and hnRNP A1 interaction and nucleocytoplasmic shuttling of p17. In this work, the interaction site of p17 with lamin A/C was mapped within the amino terminus (aa 41 to 60) of p17 and p17 colocalized with lamin A/C at the nuclear envelope. Knockdown of hnRNP A1 or lamin A/C led to inhibition of nucleocytoplasmic shuttling of p17 and reduced virus yield. Collectively, the results of this study provide mechanistic insights into hnRNP A1 and lamin A/Cmodulated nucleocytoplasmic shuttling of the ARV p17 protein.IMPORTANCE Avian reoviruses (ARVs) cause considerable economic losses in the poultry industry. The ARV p17 protein continuously shuttles between the nucleus and the cytoplasm to regulate several cellular signaling pathways and interacts with several cellular proteins to cause translation shutoff, cell cycle arrest, and autophagosome formation, all of which enhance virus replication. To date the mechanisms underlying nucleocytoplasmic shuttling of p17 remain largely unknown. Here we report that hnRNP A1 and lamin A/C serve as carrier and mediator proteins to modulate nucleocytoplasmic shuttling of p17. The formation of p17-hnRNP A1-transportin 1 carrier-cargo complex is required to modulate p17 nuclear import. Furthermore, we have identified an NES-containing nucleocytoplasmic shuttling domain (aa 19 to 40) of p17 that is critical for binding to hnRNP A1 and for nucleocytoplasmic shuttling of p17. This study provides novel insights into how hnRNP A1 and lamin A/C modulate nucleocytoplasmic shuttling of the ARV p17 protein. RESULTSCellular proteins hnRNP A1 and lamin A/C coimmunoprecipatate with p17. As shown previously, we identified several cellular proteins, such as nucleoporin Tpr, vimentin, and lamin A/C, that interact with the ARV p17 protein (27,28,30). To explore whether and how cellular proteins are involved in mediating nucleocytoplasmic shut-Chiu et al. FIG 1 p17 interacts with hnRNP A1. (A) Identification of poten...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Chiu

Huang

Wang

et al. 2019

J Virol

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“…C). O‐GlcNAc‐induced nuclear translocation of other proteins besides hnRNP‐K has also been observed, for example, NF‐kB in CCA (Phoomak et al ., ) and lung cancer (Yang et al ., ); hnRNP‐A1 (Roth and Khalaila, ) and β‐catenin in colorectal cancer (Olivier‐Van Stichelen et al ., ).…”

Section: Discussionmentioning

confidence: 99%

O‐GlcNAc‐induced nuclear translocation of hnRNP‐K is associated with progression and metastasis of cholangiocarcinoma

et al. 2019

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O‐GlcNAcylation is a key post‐translational modification that modifies the functions of proteins. Associations between O‐GlcNAcylation, shorter survival of cholangiocarcinoma (CCA) patients, and increased migration/invasion of CCA cell lines have been reported. However, the specific O‐GlcNAcylated proteins (OGPs) that participate in promotion of CCA progression are poorly understood. OGPs were isolated from human CCA cell lines, KKU‐213 and KKU‐214, using a click chemistry‐based enzymatic labeling system, identified using LC‐MS/MS, and searched against an OGP database. From the proteomic analysis, a total of 21 OGPs related to cancer progression were identified, of which 12 have not been previously reported. Among these, hnRNP‐K, a multifaceted RNA‐ and DNA‐binding protein known as a pre‐mRNA‐binding protein, was one of the most abundantly expressed, suggesting its involvement in CCA progression. O‐GlcNAcylation of hnRNP‐K was further verified by anti‐OGP/anti‐hnRNP‐K immunoprecipitations and sWGA pull‐down assays. The perpetuation of CCA by hnRNP‐K was evaluated using siRNA, which revealed modulation of cyclin D1, XIAP, EMT markers, and MMP2 and MMP7 expression. In native CCA cells, hnRNP‐K was primarily localized in the nucleus; however, when O‐GlcNAcylation was suppressed, hnRNP‐K was retained in the cytoplasm. These data signify an association between nuclear accumulation of hnRNP‐K and the migratory capabilities of CCA cells. In human CCA tissues, expression of nuclear hnRNP‐K was positively correlated with high O‐GlcNAcylation levels, metastatic stage, and shorter survival of CCA patients. This study demonstrates the significance of O‐GlcNAcylation on the nuclear translocation of hnRNP‐K and its impact on the progression of CCA.

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“…An interesting target protein that is both phosphorylated and O-GlcNAcylated is Tau, and curiously, loss of O-GlcNAcylation in forebrain neurons induces progressive neurodegeneration, an increased production of hyperphosphorylated Tau and Tau aggregation (145). Another example is hnRNP-A1, whose nucleocytoplasmic localization is regulated by phosphorylation and O-GlcNAcylation (135,146). It will be interesting to study the role of O-GlcNAcylation on Tau and hnRNP-A1 phase separation and SG association, and how both types of PTM (and possibly other PTMs) coordinately regulate the phase separation and aggregation behavior of these disease-linked proteins.…”

Section: Interplay Of Arginine Methylation and Phosphorylation With Omentioning

confidence: 99%

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

Hofweber¹,

Dormann

2019

Journal of Biological Chemistry

306

294

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Edited by Paul E. FraserRibonucleoprotein (RNP) granules are membrane-less organelles consisting of RNA-binding proteins (RBPs) and RNA. RNA granules form through liquid-liquid phase separation (LLPS), whereby weak promiscuous interactions among RBPs and/or RNAs create a dense network of interacting macromolecules and drive the phase separation. Post-translational modifications (PTMs) of RBPs have emerged as important regulators of LLPS and RNP granule dynamics, as they can directly weaken or enhance the multivalent interactions between phase-separating macromolecules or can recruit or exclude certain macromolecules into or from condensates. Here, we review recent insights into how PTMs regulate phase separation and RNP granule dynamics, in particular arginine (Arg)-methylation and phosphorylation. We discuss how these PTMs regulate the phase behavior of prototypical RBPs and how, as "friend or foe," they might influence the assembly, disassembly, or material properties of cellular RNP granules, such as stress granules or amyloidlike condensates. We particularly highlight how PTMs control the phase separation and aggregation behavior of disease-linked RBPs. We also review how disruptions of PTMs might be involved in aberrant phase transitions and the formation of amyloid-like protein aggregates as observed in neurodegenerative diseases.

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The effect of O -GlcNAcylation on hnRNP A1 translocation and interaction with transportin1

Cited by 23 publications

References 48 publications

Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

O‐GlcNAc‐induced nuclear translocation of hnRNP‐K is associated with progression and metastasis of cholangiocarcinoma

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

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