scholarly journals A bivalent supramolecular GCP‐ligand enables blocking of the Taspase1/Importin α interaction.

ChemMedChem ◽  
2021 ◽  
Author(s):  
Alexander Höing ◽  
Alexander Zimmermann ◽  
Lisa Moews ◽  
Matthias Killa ◽  
Marius Heimann ◽  
...  
Keyword(s):  
Importin Α

scholarly journals Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wen Juan Tu ◽  
Robert D. McCuaig ◽  
Michelle Melino ◽  
Daniel J. Rawle ◽  
Thuy T. Le ◽  
...  
Keyword(s):  
Viral Replication ◽  
Treatment Options ◽  
Critical Role ◽  
Post Exposure Prophylaxis ◽  
Nuclear Entry ◽  
Importin Α ◽  
Active Transcription ◽  
Nuclear Shuttling ◽  
Asymptomatic Phase ◽  
Exposure Prophylaxis

AbstractTreatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

scholarly journals Tick Importin-α Is Implicated in the Interactome and Regulome of the Cofactor Subolesin

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 457
Author(s):  
Sara Artigas-Jerónimo ◽  
Margarita Villar ◽  
Alejandro Cabezas-Cruz ◽  
Grégory Caignard ◽  
Damien Vitour ◽  
...  
Keyword(s):  
Rational Design ◽  
Fat Body ◽  
Animal Health ◽  
Direct Interaction ◽  
Vaccine Antigen ◽  
Tick Feeding ◽  
Interacting Protein ◽  
Expression Levels ◽  
Importin Α

Ticks and tick-borne diseases (TBDs) represent a burden for human and animal health worldwide. Currently, vaccines constitute the safest and most effective approach to control ticks and TBDs. Subolesin (SUB) has been identified as a vaccine antigen for the control of tick infestations and pathogen infection and transmission. The characterization of the molecular function of SUB and the identification of tick proteins interacting with SUB may provide the basis for the discovery of novel antigens and for the rational design of novel anti-tick vaccines. In the present study, we used the yeast two-hybrid system (Y2H) as an unbiased approach to identify tick SUB-interacting proteins in an Ixodes ricinus cDNA library, and studied the possible role of SUB as a chromatin remodeler through direct interaction with histones. The Y2H screening identified Importin-α as a potential SUB-interacting protein, which was confirmed in vitro in a protein pull-down assay. The sub gene expression levels in tick midgut and fat body were significantly higher in unfed than fed female ticks, however, the importin-α expression levels did not vary between unfed and fed ticks but tended to be higher in the ovary when compared to those in other organs. The effect of importin-α RNAi was characterized in I. ricinus under artificial feeding conditions. Both sub and importin-α gene knockdown was observed in all tick tissues and, while tick weight was significantly lower in sub RNAi-treated ticks than in controls, importin-α RNAi did not affect tick feeding or oviposition, suggesting that SUB is able to exert its function in the absence of Importin-α. Furthermore, SUB was shown to physically interact with histone 4, which was corroborated by protein pull-down and western blot analysis. These results confirm that by interacting with numerous tick proteins, SUB is a key cofactor of the tick interactome and regulome. Further studies are needed to elucidate the nature of the SUB-Importin-α interaction and the biological processes and functional implications that this interaction may have.

scholarly journals The nucleocapsid protein of rice stripe virus in cell nuclei of vector insect regulates viral replication

2021 ◽  
Author(s):  
Wan Zhao ◽  
Junjie Zhu ◽  
Hong Lu ◽  
Jiaming Zhu ◽  
Fei Jiang ◽  
...  
Keyword(s):  
Viral Replication ◽  
Nucleocapsid Protein ◽  
Brown Planthopper ◽  
Rice Stripe Virus ◽  
Host Cells ◽  
Cell Nuclei ◽  
Nuclear Entry ◽  
Genomic Rnas ◽  
Importin Α ◽  
Vector Insect

AbstractRice stripe virus (RSV) transmitted by the small brown planthopper causes severe rice yield losses in Asian countries. Although viral nuclear entry promotes viral replication in host cells, whether this phenomenon occurs in vector cells remains unknown. Therefore, in this study, we systematically evaluated the presence and roles of RSV in the nuclei of vector insect cells. We observed that the nucleocapsid protein (NP) and viral genomic RNAs were partially transported into vector cell nuclei by utilizing the importin α nuclear transport system. When blocking NP nuclear localization, cytoplasmic RSV accumulation significantly increased. In the vector cell nuclei, NP bound the transcription factor YY1 and affected its positive regulation to FAIM. Subsequently, decreased FAIM expression triggered an antiviral caspase-dependent apoptotic reaction. Our results reveal that viral nuclear entry induces completely different immune effects in vector and host cells, providing new insights into the balance between viral load and the immunity pressure in vector insects.

scholarly journals Transcriptional regulation of importin-α1 by JunD modulates subcellular localization of RNA-binding protein HuR in intestinal epithelial cells

2016 ◽  
Vol 311 (6) ◽  
pp. C874-C883 ◽  
Author(s):  
Yan Xu ◽  
Jie Chen ◽  
Lan Xiao ◽  
Hee Kyoung Chung ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Subcellular Localization ◽  
Rna Binding ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Intestinal Epithelial ◽  
Mucosal Regeneration ◽  
Importin Α

The RNA-binding protein HuR is crucial for normal intestinal mucosal regeneration by modulating the stability and translation of target mRNAs, but the exact mechanism underlying HuR trafficking between the cytoplasm and nucleus remains largely unknown. Here we report a novel function of transcription factor JunD in the regulation of HuR subcellular localization through the control of importin-α1 expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically inhibited importin-α1 at the transcription level, and this repression is mediated via interaction with CREB-binding site that was located at the proximal region of importin-α1 promoter. Reduction in the levels of importin-α1 by JunD increased cytoplasmic levels of HuR, although it failed to alter whole cell HuR levels. Increased levels of endogenous JunD by depleting cellular polyamines also inhibited importin-α1 expression and increased cytoplasmic HuR levels, whereas JunD silencing rescued importin-α1 expression and enhanced HuR nuclear translocation in polyamine-deficient cells. Moreover, importin-α1 silencing protected IECs against apoptosis, which was prevented by HuR silencing. These results indicate that JunD regulates HuR subcellular distribution by downregulating importin-α1, thus contributing to the maintenance of gut epithelium homeostasis.

scholarly journals mDia2 Shuttles between the Nucleus and the Cytoplasm through the Importin-α/β- and CRM1-mediated Nuclear Transport Mechanism

2008 ◽  
Vol 284 (9) ◽  
pp. 5753-5762 ◽  
Author(s):  
Takashi Miki ◽  
Katsuya Okawa ◽  
Toshihiro Sekimoto ◽  
Yoshihiro Yoneda ◽  
Sadanori Watanabe ◽  
...  
Keyword(s):  
Transport Mechanism ◽  
Nuclear Transport ◽  
Importin Α

Structural insights into the novel ARM-repeat protein CTNNBL1 and its association with the hPrp19–CDC5L complex

2014 ◽  
Vol 70 (3) ◽  
pp. 780-788 ◽  
Author(s):  
Jae-Woo Ahn ◽  
Sangwoo Kim ◽  
Eun-Jung Kim ◽  
Yeo-Jin Kim ◽  
Kyung-Jin Kim
Keyword(s):  
Crystal Structure ◽  
The Novel ◽  
Molecular Architecture ◽  
Repeat Protein ◽  
Binding Partner ◽  
Catalytic Activation ◽  
Repeat Structure ◽  
Repeat Domain ◽  
Importin Α ◽  
Structural Insights

The hPrp19–CDC5L complex plays a crucial role during human pre-mRNA splicing by catalytic activation of the spliceosome. In order to elucidate the molecular architecture of the hPrp19–CDC5L complex, the crystal structure of CTNNBL1, one of the major components of this complex, was determined. Unlike canonical ARM-repeat proteins such as β-catenin and importin-α, CTNNBL1 was found to contain a twisted and extended ARM-repeat structure at the C-terminal domain and, more importantly, the protein formed a stable dimer. A highly negatively charged patch formed in the N-terminal ARM-repeat domain of CTNNBL1 provides a binding site for CDC5L, a binding partner of the protein in the hPrp19–CDC5L complex, and these two proteins form a complex with a stoichiometry of 2:2. These findings not only present the crystal structure of a novel ARM-repeat protein, CTNNBL1, but also provide insights into the detailed molecular architecture of the hPrp19–CDC5L complex.

scholarly journals Nuclear import factors importin α and importin β undergo mutually induced conformational changes upon association

FEBS Letters ◽  
2000 ◽  
Vol 484 (3) ◽  
pp. 291-298 ◽  
Author(s):  
Gino Cingolani ◽  
Hilal A. Lashuel ◽  
Larry Gerace ◽  
Christoph W. Müller
Keyword(s):  
Conformational Changes ◽  
Nuclear Import ◽  
Importin Α

scholarly journals Structural Basis of Importin-α-Mediated Nuclear Transport for Ku70 and Ku80

2011 ◽  
Vol 412 (2) ◽  
pp. 226-234 ◽  
Author(s):  
Agnes A.S. Takeda ◽  
Andrea C. de Barros ◽  
Chiung-Wen Chang ◽  
Boštjan Kobe ◽  
Marcos R.M. Fontes
Keyword(s):  
Nuclear Transport ◽  
Structural Basis ◽  
Importin Α
Sign in / Sign up

Export Citation Format

Share Document