A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport

Porter, Frederick; Bochkov, Yury A.; Albee, Alison J.; Wiese, Christiane; Palmenberg, Ann C.

doi:10.1073/pnas.0605375103

Cited by 105 publications

(153 citation statements)

References 34 publications

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“…If conformation plays a role in L M activity, outside of the zinc finger, it must be induced by the relevant binding partners. Indeed, when bound to Ran, L M 0P condensed and made specific contacts in the central hinge and acidic domains, via the same residues identified by mutagenesis (15,24). Surprisingly, however, the amino third of the protein, including the zinc finger, and both internal phosphorylation sites were left solvent exposed.…”

Section: Discussionmentioning

confidence: 99%

“…In cell-free assays with intact nuclei, within 5 min of the introduction of recombinant L E -GST (or GST-L E ), there is complete inhibition of all active import and export of host proteins and RNA through the nuclear pore complexes (NPCs) (24). The discovery that L E bound RanGTPase, the key regulator of nucleocytoplasmic trafficking (NCT), raised the initial possibility of putative stoichiometric inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…All these tails (RMSD, 4.9 Å) had the same central helix (aa 196-206), but none were similarly oriented relative to the core. Among Ran structures solved by crystallography, the COOH tail arrangements can vary according to nucleotide status and binding partner-induced shifts that may also involve the nucleotideproximal phosphate binding P-loop (aa [16][17][18][19][20][21][22][23][24][25], Switch 1 (aa 32-45), Switch 2 (aa 66-79), and basic patch (aa 139-142) internal core segments (Fig. 3) …”

Section: Significancementioning

confidence: 99%

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Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase

Bacot‐Davis

Ciomperlik

Basta

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cardiovirus Leader (L) proteins induce potent antihost inhibition of active cellular nucleocytoplasmic trafficking by triggering aberrant hyperphosphorylation of nuclear pore proteins (Nup). To achieve this, L binds protein RanGTPase (Ran), a key trafficking regulator, and diverts it into tertiary or quaternary complexes with required kinases. The activity of L is regulated by two phosphorylation events not required for Ran binding. Matched NMR studies on the unphosphorylated, singly, and doubly phosphorylated variants of Mengovirus L (L M ) show both modifications act together to partially stabilize a short internal α-helix comprising L M residues 43-46. This motif implies that ionic and Van der Waals forces contributed by phosphorylation help organize downstream residues 48-67 into a new interface. The full structure of L M as bound to Ran (unlabeled) and Ran (216 aa

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase

Bacot‐Davis

Ciomperlik

Basta

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies of cardioviruses have focused attention on the L protein because of its multiple functions and importance in disease pathogenesis. In addition to its effect on apoptosis, cardiovirus L has been found to inhibit type I IFN transcription (13,23) and nucleocytoplasmic transport (which causes a block in mRNA egress the nucleus and therefore blocks host cell translation) (8,17). We recently found that although DA L and GDVII L both block type IFN transcription, they block at different steps in the IFNdependent IRF-3 pathway (23).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, EMCV L has been found to interfere with the apoptotic pathway downstream of caspase activation in EMCV infections of HeLa cells (18). The degree of apoptosis in different cell types may be related to the following: the timing of nonapoptotic lysis vis-à-vis apoptosis in a TMEV-infection, the interference by L of nucleocytoplasmic transport (8,17) in a particular cell type, and the absence of a component of an apoptotic pathway in a particular cell type following TMEV L expression. Fan et al found evidence of apoptosis in BHK-21 cells induced by BeAn L (9); however, this study examined only markers for apoptosis that are upstream of TUNEL staining.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Stavrou¹,

Ghadge²

2011

J Virol

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Viruses frequently have genes with proapoptotic or antiapoptotic activity that may vary in different cell types. The apoptosis that is induced can trigger either a protective or destructive immune response, thereby facilitating virus clearance or persistence of the virus. Apoptotic and antiapoptotic genes have been identified in a number of picornaviruses (reviewed in reference 1). Genes regulating apoptosis in Theiler's murine encephalomyelitis virus (TMEV) have been of special interest because of their potential importance in the pathogenesis of TMEV-induced diseases (reviewed in reference 16).TMEV is a member of the Theilovirus species of the Cardiovirus genus of the Picornaviridae; the Cardiovirus genus also includes the Encephalomyocarditis virus (EMCV) species, which comprises EMCV and mengovirus. TMEV strains can be divided into two subgroups on the basis of their differing biological properties. The GDVII strain and other members of the GDVII subgroup of TMEV are highly virulent and produce a fatal, acute polioencephalomyelitis in mice with no persistence of the virus. In contrast, DA, BeAn, and other members of the less-virulent TO subgroup induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, TMEV-induced demyelinating disease (TMEV-IDD), with persistence of the virus in the central nervous system (CNS) for the life of the mouse. During TMEV-IDD, relatively large amounts of the TMEV genome persist in oligodendrocytes and microglia, with low levels of infectious virus and viral antigen, i.e., there is a restricted expression of DA viral proteins. TMEV-IDD serves as a model of multiple sclerosis because of the similarity in the demyelinating pathology and because the immune system appears to contribute to pathology in both disorders. The remarkable disease phenotype of TO subgroup strains has made TMEV a subject of continuing interest.Apoptosis has been described during early infection of mice with strains from both subgroups of TMEV and during the late TMEV-IDD. During TMEV-IDD, apoptosis of T cells, microglia/macrophages, and oligodendrocytes has been described (2,5,20,26). In vitro studies have implicated the cardiovirus L protein, which is encoded between the start of the polyprotein and the P1 capsid proteins (Fig. 1), in regulating apoptosis. In vitro studies of TMEV carried out by Fan et al. (9) showed that transfection of an expression construct of BeAn L into BHK-21 cells and a mouse macrophage cell line led to cell death and apoptosis, while Romanova et al. (18) found that L of other cardioviruses has antiapoptotic activity, since infection with a mengovirus with a mutation in the L zinc-binding domain led to apoptosis of HeLa cells that was not seen following wild-type (wt) mengovirus infection. In order to clarify the latter observations and further characterize the apoptotic activity of TMEV, we investigated apoptosis in different cell types following transfection of DA and GDVII L expression constructs and following infection ...

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Functional roles of HIV-1 Tat protein in the nucleus

Musinova

Sheval

Dib³

et al. 2015

Cell. Mol. Life Sci.

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Human immunodeficiency virus-1 (HIV-1) Tat protein is one of the most important regulatory proteins for viral gene expression in the host cell and can modulate different cellular processes. In addition, Tat is secreted by the infected cell and can be internalized by neighboring cells; therefore, it affects both infected and uninfected cells. Tat can modulate cellular processes by interacting with different cellular structures and signaling pathways. In the nucleus, Tat might be localized either in the nucleoplasm or the nucleolus depending on its concentration. Here we review the distinct functions of Tat in the nucleoplasm and the nucleolus in connection with viral infection and HIV-induced oncogenesis.

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A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport

Cited by 105 publications

References 34 publications

Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase

Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Functional roles of HIV-1 Tat protein in the nucleus

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