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      Regulation of nucleocytoplasmic trafficking of viral proteins: An integral role in pathogenesis?

      review-article
      a , a , b , *
      Biochimica et Biophysica Acta. Molecular Cell Research
      Elsevier B.V.
      BPV, bovine papillomavirus, BRAP2, BRCA1-associated protein 2, CAV, chicken anaemia virus, CBP, CREB binding protein, Cdk, cyclin dependent kinase, CK1, protein kinase CK1, CK2, protein kinase CK2, Crm1, chromosome region maintenance protein 1, CTD, C-terminal domain, DLC, dynein light chain, DLC-AS, DLC-association sequence, dsDNA-PK, double stranded DNA-dependent protein kinase, EBV, Epstein–Barr virus, EXP, exportin, FG, phenylalanine–glycine, GSK3, glycogen synthase kinase 3, HCMV, human cytomegalovirus, HPV, human papilloma virus, HTLV, human T-cell leukaemia virus, IFN, interferon, IMP, importin, KSHV, Kaposi's sarcoma-associated herpes virus, MT, microtubule, MT-AS, MT-association sequence, LANA2, latency associated nuclear antigen 2, NE, nuclear envelope, NES, nuclear export sequence, NLS, nuclear localisation sequence, NPC, nuclear pore complex, Nup, nucleoporin, PKA, protein kinase A PKC, protein kinase C, PKC, protein kinase C, PML, promyelocytic leukaemia protein, Rb, retinoblastoma, RbBS, retinoblastoma binding site, RPP, Rabies virus phospho-protein, RV, Rabies virus, SARS, severe acute respiratory syndrome, STAT, signal transducer and activator of transcription, SV40, simian virus 40, T-ag, large tumour antigen, VZV, varicella zoster virus, Simian virus 40 T-ag, Human cytomegalovirus ppUL44, Human papillomavirus E1, Rabies virus P, Phosphorylation, Nuclear import

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          Abstract

          Signal-dependent targeting of proteins into and out of the nucleus is mediated by members of the importin (IMP) family of transport receptors, which recognise targeting signals within a cargo protein and mediate passage through the nuclear envelope-embedded nuclear pore complexes. Regulation of this process is paramount to processes such as cell division and differentiation, but is also critically important for viral replication and pathogenesis; phosphorylation appears to play a major role in regulating viral protein nucleocytoplasmic trafficking, along with other posttranslational modifications. This review focuses on viral proteins that utilise the host cell IMP machinery in order to traffic into/out of the nucleus, and in particular those where trafficking is critical to viral replication and/or pathogenesis, such as simian virus SV40 large tumour antigen (T-ag), human papilloma virus E1 protein, human cytomegalovirus processivity factor ppUL44, and various gene products from RNA viruses such as Rabies. Understanding of the mechanisms regulating viral protein nucleocytoplasmic trafficking is paramount to the future development of urgently needed specific and effective anti-viral therapeutics. This article was originally intended for the special issue “Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import”. The Publisher apologizes for any inconvenience caused.

          Research highlights

          ► Nucleocytoplasmic trafficking of viral proteins is central to viral infection. ► Posttranslational modification is a key means to regulate viral protein trafficking. ► Nuclear trafficking of viral proteins can be a target for development of anti-virals.

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          Most cited references197

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          Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.

          The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.
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            Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane.

            The host innate immune response is an important deterrent of severe viral infection in humans and animals. Nuclear import factors function as key gatekeepers that regulate the transport of innate immune regulatory cargo to the nucleus of cells to activate the antiviral response. Using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model, we demonstrate that SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention of import factors at the ER/Golgi membrane leads to a loss of STAT1 transport into the nucleus in response to interferon signaling, thus blocking the expression of STAT1-activated genes that establish an antiviral state. We mapped the region of ORF6, which binds karyopherin alpha 2, to the C terminus of ORF6 and show that mutations in the C terminus no longer bind karyopherin alpha 2 or block the nuclear import of STAT1. We also show that N-terminal deletions of karyopherin alpha 2 that no longer bind to karyopherin beta 1 still retain ORF6 binding activity but no longer block STAT1 nuclear import. Recombinant SARS-CoV lacking ORF6 did not tether karyopherin alpha 2 to the ER/Golgi membrane and allowed the import of the STAT1 complex into the nucleus. We discuss the likely implications of these data on SARS-CoV replication and pathogenesis.
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              Ubiquitination regulates PTEN nuclear import and tumor suppression.

              The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN.
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                Author and article information

                Contributors
                Journal
                Biochim Biophys Acta Mol Cell Res
                Biochim Biophys Acta Mol Cell Res
                Biochimica et Biophysica Acta. Molecular Cell Research
                Elsevier B.V.
                0167-4889
                1879-2596
                16 April 2011
                December 2011
                16 April 2011
                : 1813
                : 12
                : 2176-2190
                Affiliations
                [a ]Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Victoria, Clayton, Australia
                [b ]ARC Centre of Excellence for Biotechnology and Development, Melbourne, VIC 3000, Australia
                Author notes
                [* ]Corresponding author at: c/- Nuclear Signalling Laboratory, Dept. of Biochemistry and Molecular Biology, Monash University Building 77, Monash, VIC 3800, Australia. Tel.: + 61 3/99029341; fax: + 61 3/99029500. David.Jans@ 123456monash.edu
                Article
                S0167-4889(11)00114-5
                10.1016/j.bbamcr.2011.03.019
                7114211
                21530593
                0c5aeeaa-a39f-46a3-871d-9bada9c1e23b
                Copyright © 2011 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 16 September 2010
                : 15 March 2011
                : 30 March 2011
                Categories
                Article

                bpv, bovine papillomavirus,brap2, brca1-associated protein 2,cav, chicken anaemia virus,cbp, creb binding protein,cdk, cyclin dependent kinase,ck1, protein kinase ck1,ck2, protein kinase ck2,crm1, chromosome region maintenance protein 1,ctd, c-terminal domain,dlc, dynein light chain,dlc-as, dlc-association sequence,dsdna-pk, double stranded dna-dependent protein kinase,ebv, epstein–barr virus,exp, exportin,fg, phenylalanine–glycine,gsk3, glycogen synthase kinase 3,hcmv, human cytomegalovirus,hpv, human papilloma virus,htlv, human t-cell leukaemia virus,ifn, interferon,imp, importin,kshv, kaposi's sarcoma-associated herpes virus,mt, microtubule,mt-as, mt-association sequence,lana2, latency associated nuclear antigen 2,ne, nuclear envelope,nes, nuclear export sequence,nls, nuclear localisation sequence,npc, nuclear pore complex,nup, nucleoporin,pka, protein kinase a pkc, protein kinase c,pkc, protein kinase c,pml, promyelocytic leukaemia protein,rb, retinoblastoma,rbbs, retinoblastoma binding site,rpp, rabies virus phospho-protein,rv, rabies virus,sars, severe acute respiratory syndrome,stat, signal transducer and activator of transcription,sv40, simian virus 40,t-ag, large tumour antigen,vzv, varicella zoster virus,simian virus 40 t-ag,human cytomegalovirus ppul44,human papillomavirus e1,rabies virus p,phosphorylation,nuclear import

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