Viral Interplay with the Host Sumoylation System

Wilson, Van G.

doi:10.1007/978-3-319-50044-7_21

Cited by 26 publications

(25 citation statements)

References 220 publications

(278 reference statements)

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“…Interestingly, oncogenic viral infections can also increase metabolic and proangiogenic markers through expression of a very specific domain that also controls SUMO enzymes expression (Pozzebon et al, 2013). Viral exploitation of SUMOylation has been recently detailed in elegant reviews Lowrey et al, 2017;Wilson, 2017), to which readers can refer. In the following sections we will provide some classic examples on how oncogenic viruses impact SUMOylation to increase their ability to infect, persist, and transform host cells.…”

Section: Sumo In Dna Damagementioning

confidence: 99%

Recent Highlights: Onco Viral Exploitation of the SUMO System

Mattoscio¹,

Medda²,

Chiocca³

2020

Current Issues in Molecular Biology

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Small ubiquitin-like modifier (SUMO)ylation is a crucial post-translational modification that controls functions of a wide collection of proteins and biological processes. Hence, given its pleiotropic role, viruses have developed many approaches to usurp SUMO conjugation to exploit the cellular host environment for their own benefit. Consistently, cancer cells also frequently impact on SUMO to force cellular transformation, underlining the importance of SUMO in health and diseases. Therefore, after a brief introduction to the multistep SUMOylation pathway, in this review we will focus our attention on several examples of strategies adopted by oncogenic viruses to hijack SUMOylation in order to promote infection, persistence and malignant transformation of host cells.caister.com/cimb Curr. Figure 3.1 The SUMO conjugation system. Ulp1/SENP proteases catalyse cleavage of the C-terminal domain of SUMO proteins, exposing a diglycine motif.Processed SUMO is transferred to a cysteine of the heterodimeric E1 enzyme Uba2/SAE1. SUMO is then conjugated to a cysteine of UBC9, the E2 enzyme and attached to a lysine residue of the consensus motif on target proteins. The conjugation is often facilitated by an E3-ligase, which enforces the interactions among the involved components. SUMOylation is a reversible pathway where the Ulp1/SENPs proteases dictate the de-SUMOylation process.caister.com/cimb 2 Curr. Issues Mol. Biol. Vol. 35Oncoviruses and SUMOylation | 37

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Section: Sumo In Dna Damagementioning

confidence: 99%

Recent Highlights: Onco Viral Exploitation of the SUMO System

Mattoscio¹,

Medda²,

Chiocca³

2020

Current Issues in Molecular Biology

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“…ARKL1 was first identified as a SUMO-interacting protein (75,76) and was also shown to be highly modified by SUMO2 in response to influenza A virus infection (49). SUMOylation is central to antiviral responses, and conversely, manipulation of the SUMO pathway is a strategy employed by many viruses to regulate antiviral responses and promote infections (77)(78)(79). It is currently unclear how SUMOylation of ARKL1 (as observed in response to influenza virus infection) affects ARKL1 activity and whether SUMOylation of ARKL1 impacts EBV reactivation.…”

Section: Figmentioning

confidence: 99%

“…It is currently unclear how SUMOylation of ARKL1 (as observed in response to influenza virus infection) affects ARKL1 activity and whether SUMOylation of ARKL1 impacts EBV reactivation. However, SUMOylation in general promotes latency of EBV and other herpesviruses and must be overcome during reactivation (78,80,81), suggesting that SUMO modification of ARKL1 might be required to repress EBV reactivation. The mechanism by which ARKL1 represses Jun activity also remains to be determined.…”

Section: Figmentioning

confidence: 99%

Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation

Siddiqi

Vaidya

et al. 2019

J Virol

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Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication. Lytic reactivation starts with derepression of the Zp promoter controlling BZLF1 gene expression, which binds and is activated by the c-Jun transcriptional activator. Here, we identified the cellular Arkadia-like 1 (ARKL1) protein as a negative regulator of Zp and EBV reactivation. Silencing of ARKL1 in the context of EBV-positive gastric carcinoma (AGS) cells, nasopharyngeal carcinoma (NPC43) cells, and B (M81) cells led to increased lytic protein expression, whereas overexpression inhibited BZLF1 expression. Similar effects of ARKL1 modulation were seen on BZLF1 transcripts as well as on Zp activity in Zp reporter assays, showing that ARKL1 repressed Zp. Proteomic profiling of ARKL1-host interactions identified c-Jun as an ARKL1 interactor, and reporter assays for Jun transcriptional activity showed that ARKL1 inhibited Jun activity. The ARKL1-Jun interaction required ARKL1 sequences that we previously showed mediated binding to the CK2 kinase regulatory subunit CK2β, suggesting that CK2β might mediate the ARKL1-Jun interaction. This model was supported by the findings that silencing of CK2β, but not the CK2α catalytic subunit, abrogated the ARKL1-Jun interaction and phenocopied ARKL1 silencing in promoting EBV reactivation. Additionally, ARKL1 was associated with Zp in reporter assays and this was increased by additional CK2β. Together, the data indicate that ARKL1 is a negative regulator of Zp and EBV reactivation that acts by inhibiting Jun activity through a CK2β-mediated interaction. IMPORTANCE Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication and is associated with several types of cancer. We have identified a cellular protein (ARKL1) that acts to repress the reactivation of EBV from the latent to the lytic cycle. We show that ARKL1 acts to repress transcription of the EBV lytic switch protein by inhibiting the activity of the cellular transcription factor c-Jun. This not only provides a new mechanism of regulating EBV reactivation but also identifies a novel cellular function of ARKL1 as an inhibitor of Jun-mediated transcription.

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“…Their versatility in regulating protein function and cellular behavior makes them a particularly attractive target for viruses. One example of a key cellular regulatory system targeted by viruses is sumoylation (11,12), a posttranslational process mainly involved in nuclear functions that modifies protein function, activity, or localization of its targets through covalent attachment of a 10-kDa ubiquitinlike polypeptide called SUMO (small ubiquitin-like modifier) (13)(14)(15).…”

mentioning

confidence: 99%

“…After exertion of stress, SUMO conjugates slowly diminish by the action of ULPs, which are fundamental players in fine-tuning SUMO conjugation/deconjugation (9,10,20,33). Several observations, including pathogen manipulation of SUMO conjugation by bacterial elicitors (3,(34)(35)(36), modification of SUMO levels altering pathogen infection in plants (11,12,37,38), and sumoylation influencing innate immunity (13)(14)(15)(39)(40)(41), indicate that SUMO also plays an important role in plant defense responses.…”

mentioning

confidence: 99%

Geminivirus Replication Protein Impairs SUMO Conjugation of Proliferating Cellular Nuclear Antigen at Two Acceptor Sites

Arroyo-Mateos

Sabarit

Maio

et al. 2018

J Virol

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Geminiviruses are DNA viruses that replicate in nuclei of infected plant cells using the plant DNA replication machinery, including PCNA (Proliferating cellular nuclear antigen), a cofactor that orchestrates genome duplication and maintenance by recruiting crucial players to replication forks. These viruses encode a multifunctional protein, Rep, which is essential for viral replication, induces the accumulation of the host replication machinery and interacts with several host proteins, including PCNA and the SUMO E2 conjugation enzyme (SCE1). Post-translational modification of PCNA by ubiquitin or SUMO plays an essential role in the switching of PCNA between interacting partners during DNA metabolism processes (e.g. replication, recombination, repair, etc.). In yeast, PCNA sumoylation has been associated to DNA repair involving homologous recombination (HR). Previously, we reported that ectopic Rep expression results in very specific changes in the sumoylation pattern of plant cells. In this work, we show, using a reconstituted sumoylation system in that tomato PCNA is sumoylated at two residues, K254 and K164, and that co-expression of the geminivirus protein Rep suppresses sumoylation at these lysines. Finally, we confirm that PCNA is sumoylated and that Rep also interferes with PCNA sumoylation in plant cells.SUMO adducts have a key role in regulating the activity of animal and yeast PCNA on DNA repair and replication. Our work demonstrates for the first time that sumoylation of plant PCNA occurs in plant cells and that a plant virus interferes with this modification. This work marks the importance of sumoylation in allowing viral infection and replication in plants. Moreover, it constitutes a prime example of how viral proteins interfering with post-translational modifications of selected host factors to create a proper environment for infection.

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Viral Interplay with the Host Sumoylation System

Cited by 26 publications

References 220 publications

Recent Highlights: Onco Viral Exploitation of the SUMO System

Recent Highlights: Onco Viral Exploitation of the SUMO System

Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation

Geminivirus Replication Protein Impairs SUMO Conjugation of Proliferating Cellular Nuclear Antigen at Two Acceptor Sites

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