Sumoylation of the P Protein at K254 Plays an Important Role in Growth of Parainfluenza Virus 5

Sun, Dengyun; Xu, Ping; He, Biao

doi:10.1128/jvi.00389-11

Cited by 14 publications

(14 citation statements)

References 44 publications

(50 reference statements)

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“…Similarly, RNA interference of E2 SUMOylation enzyme Ubc9 caused a marked decrease in the production of viral proteins and the virus titer, demonstrating a relevant effect of the SUMOylation system on rotavirus replication. These results are similar to those observed with other RNA viruses where SUMO system showed to be important for virus replication (31)(32)(33). To our knowledge, this is the first demonstration of exploitation of the cellular SUMOylation machinery by a member of the Reoviridae family.…”

Section: Discussionsupporting

confidence: 79%

Rotavirus Viroplasm Proteins Interact with the Cellular SUMOylation System: Implications for Viroplasm-Like Structure Formation

Campagna

Marcos-Villar

Arnoldi

et al. 2013

J Virol

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e Posttranslational modification by SUMO provides functional flexibility to target proteins. Viruses interact extensively with the cellular SUMO modification system in order to improve their replication, and there are numerous examples of viral proteins that are SUMOylated. However, thus far the relevance of SUMOylation for rotavirus replication remains unexplored. In this study, we report that SUMOylation positively regulates rotavirus replication and viral protein production. We show that SUMO can be covalently conjugated to the viroplasm proteins VP1, VP2, NSP2, VP6, and NSP5. In addition, VP1, VP2, and NSP2 can also interact with SUMO in a noncovalent manner. We observed that an NSP5 SUMOylation mutant protein retains most of its activities, such as its interaction with VP1 and NSP2, the formation of viroplasm-like structures after the coexpression with NSP2, and the ability to complement in trans the lack of NSP5 in infected cells. However, this mutant is characterized by a high degree of phosphorylation and is impaired in the formation of viroplasm-like structures when coexpressed with VP2. These results reveal for the first time a positive role for SUMO modification in rotavirus replication, describe the SUMOylation of several viroplasm resident rotavirus proteins, and demonstrate a requirement for NSP5 SUMOylation in the production of viroplasmlike structures. Rotavirus, a member of the Reoviridae family, is the major etiological cause of severe gastroenteritis of viral origin in infants and young children. The infective virion consists of a nonenveloped triple-layered particle (TLP). Inside the inner layer, composed by pentamers of the structural protein VP2, are contained the 11 double-stranded RNA (dsRNA) segments of the viral genome, the RNA-dependent RNA polymerase VP1, and the RNA capping enzyme VP3, altogether forming the core of the virus. Around the core is present a second intermediate layer, composed by the structural protein VP6, forming a double-layered particle (DLP) that is surrounded by the third outermost layer composed by the proteins VP7 and VP4 forming the fully assembled infectious TLP.Upon virus entry in the host cell, the outermost layer of the virus is lost and DLPs become active in transcribing the viral mRNA from the dsRNA genome, acting VP1 also as a transcriptase. Even though it has been shown in vitro that the minimal requirement for viral replication is represented by VP1 and VP2 (1, 2), in vivo replication and packaging occur in viral factories, called viroplasms (3). These structures are formed, apart from VP1 and VP2, also by the other structural proteins necessary for the formation of the DLPs, VP3 and VP6, and two nonstructural proteins, NSP2 and NSP5. Both nonstructural proteins are essential for viroplasm formation and virus replication (4-6), but while NSP2 has been proposed to be the molecular motor responsible of the packaging of rotavirus genome in newly synthesized cores (7,8), the role for NSP5 is less clear. The NSP5 protein, synthesized by the smallest segment...

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Section: Discussionsupporting

confidence: 79%

Rotavirus Viroplasm Proteins Interact with the Cellular SUMOylation System: Implications for Viroplasm-Like Structure Formation

Campagna

Marcos-Villar

Arnoldi

et al. 2013

J Virol

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“…Similar observations about the role of K254 in SUMO conjugation and its importance for genome activity, mRNA synthesis, and viral protein expression have been made during virus infection (175). It therefore appears that modification of P is necessary for efficient viral transcription by the PIV5 RNA-dependent RNA polymerase, probably by recruiting as yet unknown host cell factors to the viral transcription sites.…”

Section: Rna Virusessupporting

confidence: 53%

“…The viral P protein is an essential cofactor of the viral RNA-dependent RNA polymerase, which has been shown to be modified within a classic SCM by SUMO-1, but not SUMO-2 or SUMO-3. However, since PIV5 P K254R still shows residual SUMOylation, additional conjugation sites other than K254 are likely (175).…”

Section: Rna Virusesmentioning

confidence: 99%

Human Pathogens and the Host Cell SUMOylation System

Wimmer

Schreiner

Dobner

2012

J Virol

108

101

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Since posttranslational modification (PTM) by the small ubiquitin-related modifiers (SUMOs) was discovered over a decade ago, a huge number of cellular proteins have been found to be reversibly modified, resulting in alteration of differential cellular pathways. Although the molecular consequences of SUMO attachment are difficult to predict, the underlying principle of SUMOylation is altering inter-and/or intramolecular interactions of the modified substrate, changing localization, stability, and/or activity. Unsurprisingly, many different pathogens have evolved to exploit the cellular SUMO modification system due to its functional flexibility and far-reaching functional downstream consequences. Although the extensive knowledge gained so far is impressive, a definitive conclusion about the role of SUMO modification during virus infection in general remains elusive and is still restricted to a few, yet promising concepts. Based on the available data, this review aims, first, to provide a detailed overview of the current state of knowledge and, second, to evaluate the currently known common principles/molecular mechanisms of how human pathogenic microbes, especially viruses and their regulatory proteins, exploit the host cell SUMO modification system. Small ubiquitin-related modifier (SUMO) was initially identified as reversible, proteinogenic posttranslational modification (PTM) by different laboratories in the mid-1990s (13,116,122,125,135). Today, it is classified as a member of the ubiquitin-like proteins (Ubls) due to its structural and sequence similarities to ubiquitin (89, 169); however, the surface properties of SUMO are quite distinct. Interestingly, it appears that the characteristic determinants of PTM by Ubls are phylogenetically ancient and may have evolved from biosynthetic pathways via repeated rounds of gene duplication and diversification (75). Consequently, SUMO is expressed by all eukaryotes but is absent from prokaryotes/archaea. Lower eukaryotes have a single SUMO gene, whereas plants and vertebrates express several SUMO paralogues.In vertebrates, two subfamilies, namely, SUMO-1 and SUMO-2/3 proteins, are known. SUMO-2 and SUMO-3 are commonly referred to as SUMO-2/3 due to 98% sequence similarity and the lack, to date, of clearly distinguishable functional differences. Although members of each subfamily are highly similar, SUMO-1 and SUMO-2/3 share only about 50% amino acid sequence identity, although all are ϳ100-residue proteins containing significant primary sequence homology to ubiquitin in the C terminus (ϳ20%) and a short unstructured N-terminal stretch (11,128).Recent research has shown important differences in the molecular functionalities of mammalian SUMO-1 and SUMO-2/3 proteins. The latter is present in higher levels than SUMO-1, whereas the unconjugated pool of SUMO-1 is lower than that of SUMO-2/3. Intriguingly, SUMO-2 and SUMO-3 can be conjugated to target proteins in a chain-wise fashion due to internal SUMO conjugation motifs (SCMs), whereas SUMO-1 lacks this ability. Moreover...

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“…However, in experiments with the rubulaviruses, PIV5 and mumps virus, regulatory effects of phosphorylation have been clearly demonstrated (88–90). In addition, sumoylation been shown to impact RNA synthesis (91). Given these findings, it would be interesting to determine to what extent phosphorylation and other post-translational modifications can play a role in temporal regulation.…”

Section: Part 3: Regulation Of Paramyxovirus Polymerase Activitymentioning

confidence: 99%

Initiation and regulation of paramyxovirus transcription and replication

2015

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The paramyxovirus family has a genome consisting of a single strand of negative sense RNA. This genome acts as a template for two distinct processes: transcription to generate subgenomic, capped and polyadenylated mRNAs, and genome replication. These viruses only encode one polymerase. Thus, an intriguing question is, how does the viral polymerase initiate and become committed to either transcription or replication? By answering this we can begin to understand how these two processes are regulated. In this review article, we present recent findings from studies on the paramyxovirus, respiratory syncytial virus, which show how its polymerase is able to initiate transcription and replication from a single promoter. We discuss how these findings apply to other paramyxoviruses. Then, we examine how trans-acting proteins and promoter secondary structure might serve to regulate transcription and replication during different phases of the paramyxovirus replication cycle.

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Sumoylation of the P Protein at K254 Plays an Important Role in Growth of Parainfluenza Virus 5

Cited by 14 publications

References 44 publications

Rotavirus Viroplasm Proteins Interact with the Cellular SUMOylation System: Implications for Viroplasm-Like Structure Formation

Rotavirus Viroplasm Proteins Interact with the Cellular SUMOylation System: Implications for Viroplasm-Like Structure Formation

Human Pathogens and the Host Cell SUMOylation System

Initiation and regulation of paramyxovirus transcription and replication

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