Protein arginine methylation during lytic adenovirus infection

Kzhyshkowska, Julia; Kremmer, Elisabeth; Hofmann, Markus; Wolf, Hans; Dobner, Thomas

doi:10.1042/bj20040210

Cited by 32 publications

(22 citation statements)

References 36 publications

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“…100K is known to be a phosphoprotein, although the function and the sites of phosphorylation remain to be elucidated. Moreover, 100K was recently reported to be methylated during infection of permissive tumor cells, and methylation is mediated by PRMT1, the most abundant methylase in the cell (15). However, the mechanism by which methylation controls 100K function and its importance during infection has not been determined.…”

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Critical Role for Arginine Methylation in Adenovirus-Infected Cells

Iacovides

O’Shea

Oses-Prieto

et al. 2007

J Virol

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During the late stages of adenovirus infection, the 100K protein (100K) inhibits the translation of cellular messages in the cytoplasm and regulates hexon trimerization and assembly in the nucleus. However, it is not known how it switches between these two functions. Here we show that 100K is methylated on arginine residues at its C terminus during infection and that this region is necessary for binding PRMT1 methylase. Methylated 100K is exclusively nuclear. Mutation of the third RGG motif (amino acids 741 to 743) prevents localization to the nucleus during infection, suggesting that methylation of that sequence is important for 100K shuttling. Treatment of infected cells with methylation inhibitors inhibits expression of late structural proteins. These data suggest that arginine methylation of 100K is necessary for its localization to the nucleus and is a critical cellular function necessary for productive adenovirus infection.During a productive infection, adenovirus turns the infected cell into an efficient virion-producing factory. To do this, the virus must interfere with and manipulate several cellular processes to facilitate replication and packaging of its genome into newly synthesized virions. A characteristic of the late phase of infection is the severe inhibition of cellular protein synthesis (2) and the selective translation of late viral mRNAs (28, 29). At least one viral product has been implicated in this process: the 100K nonstructural protein (11). The adenovirus type 5 (Ad5) 100K protein (referred to here as 100K) is thought to inhibit host protein synthesis by binding to EIF4F on the EIF4F translation initiation complex in the cytoplasm and preventing its phosphorylation by mnk1 kinase (5, 6). Dephosphorylation of EIF4F is believed to lead to inhibition of cellular protein synthesis (26), whereas late viral messages are preferentially translated by a process known as ribosome shunting (8).However, 100K is also involved in hexon trimerization and assembly, a part of the packaging process of the viral genomes into newly synthesized capsids that occurs in the nucleus (19), and cells infected with conditional temperature-sensitive (ts) 100K mutants show cytoplasmic accumulation of hexon monomers and fail to accumulate hexon trimers in the nucleus at the nonpermissive temperature (3,20). Therefore, 100K must be able to localize in both subcellular compartments and may switch between these two functions during infection. Recently, a Rev-like nuclear export sequence and a nuclear localization sequence (NLS) were identified within the carboxy terminus of 100K (7). Deletion of the 100K C terminus resulted in its cytoplasmic accumulation, suggesting that the NLS is within that part of the molecule. However, the mechanism by which 100K subcellular localization and function is regulated during infection is currently unknown.Posttranslational modification of proteins allows viruses to overcome the limitations imposed by the small size of their genomes, offering each viral product the capacity to expand it...

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confidence: 99%

Critical Role for Arginine Methylation in Adenovirus-Infected Cells

Iacovides

O’Shea

Oses-Prieto

et al. 2007

J Virol

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“…For this purpose, A549 cells were infected with H5pg4100 (wt) and H5pm4165 (mutant) virus. Thirty-six hours postinfection, cells were fixed with methanol and immunofluorescence analysis was performed (20), using anti-L4-100K MAb 6B10 (14). Most surprisingly, the L4-100K protein showed a predominantly cytoplasmic staining pattern in both wt-and mutant-virus-infected cells (100% of cells examined in both cases, n ϭ 61 and n ϭ 40, respectively) ( Fig.…”

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“…To detect early E2A-72K and E1B-55K proteins, monoclonal antibodies (MAb) B6-8 (12) and 2A6 (13) were used. Late L4-100K and capsid proteins were detected with MAb 6B10 (14) and anti-Ad5 rabbit polyclonal serum L133 (15), respectively. Analyses of early protein expression ( Fig.…”

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Amino Acid Exchanges in the Putative Nuclear Export Signal of Adenovirus Type 5 L4-100K Severely Reduce Viral Progeny due to Effects on Hexon Biogenesis

Koyuncu

Speiseder

Dobner

et al. 2013

J Virol

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The adenovirus type 5 nonstructural L4-100K protein is indispensable for efficient lytic infection. During the late phase, L4-100K promotes selective translation of viral late transcripts and mediates the trimerization of the major capsid protein hexon. In the present study, the role of a potential nuclear export signal in L4-100K was investigated. Intriguingly, amino acid substitutions in this sequence resulted in severely diminished progeny virus production, seemingly by precluding proper hexon biogenesis.

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“…Methylation at arginine residues of the RNA-binding motif of a small form of Hepatitis delta virus antigen is required for viral replication (25). Arginine methylation of adenovirus E1B-AP5 protein is also crucial for the virus to replicate efficiently (19). During preparation of this paper, a novel protein arginine methyltransferase in Nicotiana tabacum was reported to methylate Cucumber mosaic virus 1a protein and promote viral spread to noninoculated upper leaves (15).…”

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confidence: 99%