Human Pathogens and the Host Cell SUMOylation System

Wimmer, Peter; Schreiner, Sabrina; Dobner, Thomas

doi:10.1128/jvi.06227-11

Cited by 111 publications

(102 citation statements)

References 203 publications

(272 reference statements)

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“…Similar connections have been observed in animals, including roles in anaerobic tolerance (34,35) and genotoxic stress (36). Numerous plant and animal pathogens also have been shown to synthesize factors that promote infection by interfering with host SUMOylation (37,38).…”

mentioning

confidence: 53%

Quantitative Proteomics Reveals Factors Regulating RNA Biology as Dynamic Targets of Stress-induced SUMOylation in Arabidopsis

Miller

Scalf

Rytz

et al. 2013

Molecular & Cellular Proteomics

132

158

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The stress-induced attachment of small ubiquitin-like modifier (SUMO) to a diverse collection of nuclear proteins regulating chromatin architecture, transcription, and RNA biology has been implicated in protecting plants and animals against numerous environmental challenges. In order to better understand stress-induced SUMOylation, we combined stringent purification of SUMO conjugates with isobaric tag for relative and absolute quantification mass spectrometry and an advanced method to adjust for sample-to-sample variation so as to study quantitatively the SUMOylation dynamics of intact Arabidopsis seedlings subjected to stress. Inspection of 172 SUMO substrates during and after heat shock (37°C) revealed that stress mostly increases the abundance of existing conjugates, as opposed to modifying new targets. Some of the most robustly up-regulated targets participate in RNA processing and turnover and RNA-directed DNA modification, thus implicating SUMO as a regulator of the transcriptome during stress. Many of these targets were also strongly SUMOylated during ethanol and oxidative stress, suggesting that their modification is crucial for general stress tolerance. Collectively, our quantitative data emphasize the importance of SUMO to RNA-related processes protecting plants from adverse environments. The ability of cellular organisms to cope with environmental challenges requires the detection and immediate initiation of defense responses designed to mitigate the damage inflicted and enhance the organism's ability to tolerate future insults. For sessile organisms such as plants, robust stress responses are fundamental to their survival in a wide range of adverse environments (1, 2). Genetic and biochemical studies have identified a plethora of input pathways and output responses for stress protection in both prokaryotes and eukaryotes. Universally important is the synthesis of heat shock proteins that minimize protein aggregation and stimulate protein refolding through intrinsic chaperone activities (3).The stress-induced modification of intracellular proteins by small ubiquitin-like modifier (SUMO) 1 has recently emerged as an additional line of defense in eukaryotes (4 -6). Attachment of the ϳ100-amino-acid SUMO protein is driven by an ATPdependent, three-step enzyme cascade, which in Arabidopsis thaliana involves the E1 heterodimer (SAE2 together with either of two SAE1 isoforms), a single E2 SCE1, and at least two E3s (SAP, MIZ1 (SIZ1), and MMS21/HYP2) (7-11). The end result is the isopeptide linkage of one or more SUMO moieties to accessible target lysine(s). Most commonly, a consensus ⌿KxE SUMO-binding motif is modified, where ⌿ represents a bulky hydrophobic residue (12, 13). In some cases, the bound SUMOs themselves are also substrates, which results in poly-SUMO chains decorating the target (14, 15). Once generated, SUMO conjugates can be disassembled by a family of deSUMOylating proteases that specifically cleave these isopeptide bonds, thus allowing SUMO to act reversibly (e.g. Refs. 7,[16][17][18].Imp...

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mentioning

confidence: 53%

Quantitative Proteomics Reveals Factors Regulating RNA Biology as Dynamic Targets of Stress-induced SUMOylation in Arabidopsis

Miller

Scalf

Rytz

et al. 2013

Molecular & Cellular Proteomics

132

158

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“…A number of viral proteins have been reported to be modified by SUMO moieties (22,62). However, knowledge concerning SUMOylation in enteroviruses is limited.…”

Section: Discussionmentioning

confidence: 99%

“…However, knowledge concerning SUMOylation in enteroviruses is limited. Only EV71 3C protease is SUMOylated, while coxsackievirus B5 is involved in the host cell SUMOylation system in the family Picornaviridae (38,62,70). Current understanding of viral polymerase SUMOylation is limited to RdRp of Turnip mosaic virus (71), DNA polymerase subunit UL44 of HCMV (25), nonstructural protein 5 (NS5) of dengue virus (72), and polymerase basic protein 1 (PB1) of influenza virus (30).…”

Section: Discussionmentioning

confidence: 99%

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication

Liu

Zheng

Shu

et al. 2016

J Virol

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Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family Picornaviridae, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and in vitro. Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication. IMPORTANCEInfection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and in vitro. Moreover, the SUMOylation sites were determined, and in vitro polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication. S mall ubiquitin-like modifier (SUMO) modification, a member of the group of posttranslational modifications (PTMs), is important for the regulation of many cellular proteins and pathways (1). SUMO is a novel...

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“…Intriguingly, SUMO1 is detected mainly in the protein shell formed by PML and Sp100, whereas SUMO2/3 chains are also found in the interior of the PML-NB, mediating interactions with proteins transiently localizing to these domains (46). Since SUMO proteins regulate many different processes within the cell (45,47), it is not surprising that viral pathogens take advantage of this posttranslational modification (PTM) to manipulate cellular pathways and maintain the integrity of viral proteins (48)(49)(50).…”

Section: Importancementioning

confidence: 99%

Sp100 Isoform-Specific Regulation of Human Adenovirus 5 Gene Expression

Berscheminski

Wimmer

Brun

et al. 2014

J Virol

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Promyelocytic leukemia nuclear bodies (PML-NBs) are nuclear structures that accumulate intrinsic host factors to restrict viral infections. To ensure viral replication, these must be limited by expression of viral early regulatory proteins that functionally inhibit PML-NB-associated antiviral effects. To benefit from the activating capabilities of Sp100A and simultaneously limit repression by Sp100B, -C, and -HMG, adenoviruses (Ads) employ several features to selectively and individually target these isoforms. Ads induce relocalization of Sp100B, -C, and -HMG from PML-NBs prior to association with viral replication centers. In contrast, Sp100A is kept at the PML tracks that surround the newly formed viral replication centers as designated sites of active transcription. We concluded that the host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression. Ad-dependent loss of Sp100 SUMOylation is another crucial part of the virus repertoire to counteract intrinsic immunity by circumventing Sp100 association with HP1, therefore limiting chromatin condensation. We provide evidence that Ad selectively counteracts antiviral responses and, at the same time, benefits from PML-NB-associated components which support viral gene expression by actively recruiting them to PML track-like structures. Our findings provide insights into novel strategies for manipulating transcriptional regulation to either inactivate or amplify viral gene expression. IMPORTANCEWe describe an adenoviral evasion strategy that involves isoform-specific and active manipulation of the PML-associated restriction factor Sp100. Recently, we reported that the adenoviral transactivator E1A targets PML-II to efficiently activate viral transcription. In contrast, the PML-associated proteins Daxx and ATRX are inhibited by early viral factors. We show that this concept is more intricate and significant than originally believed, since adenoviruses apparently take advantage of specific PML-NBassociated proteins and simultaneously inhibit antiviral measures to maintain the viral infectious program. Specifically, we observed Ad-induced relocalization of the Sp100 isoforms B, C, and HMG from PML-NBs juxtaposed with viral replication centers. In contrast, Sp100A is retained at Ad-induced PML tracks that surround the newly formed viral replication centers, acting as designated sites of active transcription. The host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression.

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Human Pathogens and the Host Cell SUMOylation System

Cited by 111 publications

References 203 publications

Quantitative Proteomics Reveals Factors Regulating RNA Biology as Dynamic Targets of Stress-induced SUMOylation in Arabidopsis

Quantitative Proteomics Reveals Factors Regulating RNA Biology as Dynamic Targets of Stress-induced SUMOylation in Arabidopsis

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication

Sp100 Isoform-Specific Regulation of Human Adenovirus 5 Gene Expression

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