SUMOylation and cell signalling

Andreou, Artemisia M.; Tavernarakis, Nektarios

doi:10.1002/biot.200900219

Cited by 55 publications

(47 citation statements)

References 138 publications

(155 reference statements)

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“…LMP1-induced signaling also helps modulate the antiviral environment within latently infected cells (38)(39)(40)(41)(42)(43)(44)(45), and our recent studies highlight a role for LMP1 CTAR3-induced sumoylation in modulating this antiviral environment (46). Sumoylation processes aid in transcriptional repression (47)(48)(49), and we have reported that LMP1 CTAR3-mediated sumoylation results in transcriptional repression (46). Therefore, we hypothesize that LMP1 induces, via CTAR3, the sumoylation of cellular proteins, which collectively promote transcriptional repression and help sustain the EBV latent state.…”

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confidence: 87%

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

Bentz

Moss

Whitehurst

et al. 2015

J Virol

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As a herpesvirus, Epstein-Barr virus (EBV) establishes a latent infection that can periodically undergo reactivation, resulting in lytic replication and the production of new infectious virus. Latent membrane protein-1 (LMP1), the principal viral oncoprotein, is a latency-associated protein implicated in regulating viral reactivation and the maintenance of latency. We recently found that LMP1 hijacks the SUMO-conjugating enzyme Ubc9 via its C-terminal activating region-3 (CTAR3) and induces the sumoylation of cellular proteins. Because protein sumoylation can promote transcriptional repression, we hypothesized that LMP1-induced protein sumoylation induces the repression of EBV lytic promoters and helps maintain the viral genome in its latent state. We now show that with inhibition of LMP1-induced protein sumoylation, the latent state becomes less stable or leakier in EBVtransformed lymphoblastoid cell lines. The cells are also more sensitive to viral reactivation induced by irradiation, which results in the increased production and release of infectious virus, as well as increased susceptibility to ganciclovir treatment. We have identified a target of LMP1-mediated sumoylation that contributes to the maintenance of latency in this context: KRABassociated protein-1 (KAP1). LMP1 CTAR3-mediated sumoylation regulates the function of KAP1. KAP1 also binds to EBV OriLyt and immediate early promoters in a CTAR3-dependent manner, and inhibition of sumoylation processes abrogates the binding of KAP1 to these promoters. These data provide an additional line of evidence that supports our findings that CTAR3 is a distinct functioning regulatory region of LMP1 and confirm that LMP1-induced sumoylation may help stabilize the maintenance of EBV latency. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) plays an important role in the maintenance of viral latency. Previously, we documented that LMP1 targets cellular proteins to be modified by a ubiquitin-like protein (SUMO).We have now identified a function for this LMP1-induced modification of cellular proteins in the maintenance of EBV latency. Because latently infected cells have to undergo viral reactivation in order to be vulnerable to antiviral drugs, these findings identify a new way to increase the rate of EBV reactivation, which increases cell susceptibility to antiviral therapies. E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that causes persistent infection, generally asymptomatic, in over 90% of the world's population. Initially, the virus lytically infects oropharyngeal epithelial cells, producing virions containing linear genomes. The virus also quickly infects B lymphocytes, in which latent infection is established and persists in the form of episomes and subsets of viral latency genes are expressed. Periodically, latent virus can be reactivated and infectious virus is released in saliva (1). The processes that regulate the switch between latent and lytic infection have been studied for many years. One viral gene impli...

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confidence: 87%

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

Bentz

Moss

Whitehurst

et al. 2015

J Virol

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“…The sumoylation pathway has been implicated in the process of cellular senescence (61). There are several SUMO isoforms in mammals that differ in structure and functional activity.…”

Section: Figurementioning

confidence: 99%

Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H

Kudryashova¹,

Kramerova²,

Spencer³

2012

J. Clin. Invest.

102

112

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Mutations in the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) are responsible for the disease limb-girdle muscular dystrophy 2H (LGMD2H). Previously, we generated Trim32 knockout mice (Trim32 -/-mice) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we used these mice to investigate the muscle-specific defects arising from the absence of TRIM32, which underlie the myopathic phenotype. Using 2 models of induced atrophy, we showed that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 was necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts underwent premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase and TRIM32 substrate that was previously shown to be associated with senescence. Premature senescence of myoblasts was also observed in vivo in an atrophy/regrowth model. Trim32 -/-muscles had substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure compared with wildtype muscles. Moreover, Trim32 -/-muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These results imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal what we believe to be a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia.

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“…Many proteins, including RanGap1, Sp3, ERK, P53, IB␣, PIAS, STAT1, MDA5, and RIG-I, have been found to be covalently linked to SUMO through a process called sumoylation (7, 22, 25, 28-30, 35, 43). Sumoylated proteins are involved in transcriptional regulation, nuclear-cytosolic transport, protein stability, stress response, signal transduction, DNA repair, and the cell cycle (1,2,9,15,36,38). The reversible process of sumoylation is carried out similarly to ubiquitination through activation, conjugation, and ligation (9,15).…”

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

Sun

2011

J Virol

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The P protein of parainfluenza virus 5 (PIV5) is an essential cofactor of the viral RNA-dependent RNA polymerase. Phosphorylation of the P protein can positively or negatively regulate viral gene expression, depending on the precise phosphorylation sites. Sumoylation, a process of adding small ubiquitin-like modifier (SUMO) to proteins posttranslationally, plays an important role in regulating protein function. In this study, we have found that the P protein of PIV5 was sumoylated with SUMO1 in both transfected and infected cells. The K254 residue of the P protein is within a consensus sumoylation motif. Mutation of the P protein at K254 to arginine (P-K254R) reduced PIV5 minigenome activity, as well as the sumoylation level of the P protein. Incorporation of K254R into a recombinant PIV5 (rPIV5-P-K254R) resulted in a virus that grew to a lower titer and had lower levels of viral RNA synthesis and protein expression than wild-type PIV5, suggesting that sumoylation of the P protein at K254 is important for PIV5 growth. Biochemical studies did not reveal any defect of P-K254R in its interactions with viral proteins NP and L or formation of homotetramers. We propose that sumoylation of the P protein at K254 regulates PIV5 gene expression through a host protein.

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SUMOylation and cell signalling

Cited by 55 publications

References 138 publications

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H

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

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