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Order Blubervirales: Core Protein
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The most important targets of the HBc protein during HBV replication were the nuclei of infected cells, as the HBc protein shuttled between the nucleus and cytoplasm. The importin alpha and beta complexes, or importin alpha alone, were regarded therefore as potential transporters of capsids to the nuclear pores (Kann et al. 2007), where capsids interacted with nucleoporin 153 and dissociated during nuclear entry (Rabe et al. 2009; Schmitz et al. 2010).
Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
Recent investigations have identified cytosolic receptor proteins responsible for transport of NLS-containing proteins into the nucleus (Fig. 6) (127,128). These studies employing in vitro reconstitution of nuclear import showed that two cytosolic fractions were necessary and sufficient to reproduce nuclear protein import. Fraction A, associated with nuclear envelope docking activity, contains a protein heterodimer of importin-α and importin-β (128). Fraction B conferred nuclear pore translocation and has been shown to contain a GTPbinding protein called Ran/TC4, and an associated stimulatory factor called pp15. Görlich and colleagues have shown that Ran/TC4 and importin-α/β are sufficient to restore nuclear import. These cytosolic transport factors and their homologs have been the subject of extensive, ongoing investigations. Table 4 summarizes the transport factors identified to date.
The Cell and Cell Division
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Nuclear pores (Fig. 12) are highly specialized structures, which mediate the transfer of macromolecules across the nuclear membrane. Many proteins (e.g., the androgen receptor) contain a nuclear localization signal (NLS), which comprise short sequences of highly basic amino acids such as lysine. This NLS binds to importin-a and is actively transported into the nucleus. This whole process is driven by a concentration gradient of RAN-GTP.
Recent progress in the repurposing of drugs/molecules for the management of COVID-19
Published in Expert Review of Anti-infective Therapy, 2021
Divakar Sharma, Adinarayana Kunamneni
Ivermectin is an anti-parasitic drug (FDA-approved) that showed broad-spectrum host-centric anti-viral activity against many viruses, in-vitro [37]. It interacted with the heterodimeric importin (IMP) α/β1 and inhibited the nuclear import of key proteins host as well as viral in the coronaviruses [38,39]. An in-vitro study reported that ivermectin very efficiently cleared the SARS-CoV-2 from the infected Vero-hSLAM cells [40]. In SARS-CoV and MERS-CoV, ORF6 proteins and ORF4b proteins interacted with IMP-α respectively and access the nucleus in an NLS-dependent fashion and lead to altered mRNA splicing [41]. But ivermectin binding to IMP-α dissociated the IMP α/β1 heterodimer and block the NS5 nuclear import which further leads to normal mRNA splicing. In SARS-CoV-2 it is still unknown which ORFs protein interacted with IMP-α, various researches are ongoing in this direction. Further in-vivo research is needed to validate the in-vitro results of potential drugs against the SARS-Co-V-2. Based on these shreds of evidence ivermectin could be repurposed as a potent molecule against COVID-19.
Case-only analysis of gene–gene interactions in inflammatory bowel disease
Published in Scandinavian Journal of Gastroenterology, 2020
Milda Aleknonytė-Resch, Sandra Freitag-Wolf, Stefan Schreiber, Michael Krawczak, Astrid Dempfle
The IL27 gene on human chromosome 16, encoding Interleukin 27, is widely known to play an important role in IBD, and there is even evidence for an IL27 therapy being effective in IBD [29]. Interestingly, SNP rs26528 is also located in an enhancer (GH16J028503) that has seven target genes, including IL27. The other interacting SNP, rs9297145, is located in an intron of the KPNA7 gene on chromosome 7. This gene encodes Karyopherin Subunit Alpha 7, a member of the importin alpha family involved in nuclear protein import. As was highlighted by Pumroy and Cingolani [30], importin expression is an important regulator of NF-κB signaling, disruption of which is associated with various human conditions, including neurological and cardiovascular diseases. Most importantly, however, nucleocytoplasmic shuttling of NF-κB plays a key role in IBD pathophysiology [31]. In our current understanding, IBD is characterized by an overwhelming expression of pro-inflammatory cytokines that are expressed in signaling pathways in the gut that are controlled by NF-κB as a master regulator of gene transcription. In particular, NF-κB is targeting the IL27 gene promoter. Therefore, one plausible biological explanation of the statistical interaction observed here between SNPs rs26528 and rs9297145 could be genotype-dependent mutual tuning of the efficiency by which GH16J028503 and the NF-κB pathway control IL27 gene expression. This interpretation would raise interest in IL-27 both as a biomarker and as a therapeutic target.
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
Two nuclear localization sequences (NLS) are located in exon 11 which encode almost 60% of the BRCA1 protein. The NLS plays a role in facilitating the interaction of the protein with importin-alpha, which mediates the transport of BRCA1 from the cytosol to the nucleus. NLS mutations lead to a shift towards cytosolic localization of BRCA1, leading to increased unrepaired mutations and chromosomal abnormalities in tumors [15,16]. The BRCT domain is located between amino acids 1650–1863 and facilitates the interaction of BRCA1 with ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR) and multiple transcriptional regulators [17]. BRCT domain mutations destroy the capability of BRCA1 to interact with phosphoproteins. These mutations have been found in breast and ovarian cancers, suggesting that the BRCT domain is involved in tumor suppressor function. The BRCT has also been demonstrated to mediate interactions with proteins phosphorylated by ATM and ATR such as CtlP and BACH1 and to facilitate BRCA1 DNA-binding activity [18].