The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1

Wang, Shuai; Long, Jing; Zheng, Chunfu

doi:10.1007/s13238-012-2021-x

Cited by 20 publications

(16 citation statements)

References 130 publications

(120 reference statements)

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“…In addition to their roles in telomere stability, PML-NBs have antiviral defense functions (36), (35). In contrast to many other viruses including HSV, CMV, EBV and HHV-8, HHV-6A/B infection does not lead to the dispersal of PML-NBs but rather to PML-NBs coalescence (38), (66), (67), (68), (33). Whether this affects antiviral functions of PML-NBs remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Some viruses have developed ways to overcome this antiviral mechanism by degrading or manipulating PML-NBs. For example, herpes simplex virus 1 (HSV-1) encodes the E3 ligase ICP0 that conjugates ubiquitin to PML and induces its degradation (37), (38). Human cytomegalovirus (hCMV) IE1 de-SUMOylates PML-NBs resulting in PML redistribution (39).…”

Section: Introductionmentioning

confidence: 99%

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Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Collin

Gravel

Kaufer

et al. 2018

Preprint

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18 Human herpesviruses 6A and 6B (HHV-6A/B) are two betaherpesviruses that readily 19 integrate their genomes into the telomeres of human chromosomes. To date, the cellular 20 or viral proteins that facilitate HHV-6A/B integration remain elusive. In the present study, 21 we demonstrate that the immediate early protein 1 (IE1) of HHV-6A/B colocalizes with 22 telomeres during infection. Moreover, IE1 associates with PML-NBs, a nuclear complex 23 that regulates multiples cellular mechanism including DNA repair and antiviral responses.24 Furthermore, we could demonstrate that IE1 targets all PML isoforms and that both 25 proteins colocalize at telomeres. To determine the role of PML in HHV-6A/B integration, 26 we generated PML knockout cell lines using CRISPR/Cas9. Intriguingly, in the absence of 27 PML, the IE1 protein could still localize to telomeres albeit less frequently. More 28 importantly, HHV-6A/B integration was impaired in the absence of PML, indicating that 29 it plays a role in the integration process. Taken together, we identified the first cellular 30 protein that aids in the integration of HHV-6A/B and shed light on this targeted integration 31 mechanism. 32 33 Author summary 34 Human herpesviruses type 6A and 6B are relatively common viruses whose infections can 35 be life threatening in patients with a compromised immune system. A rather unique feature 36 of these viruses is their ability to integrate their genome in human chromosomes.37 Integration takes place is a specialized region of the chromosomes known as telomeres, a 38 region that controls cellular lifespan. To date, the mechanisms leading to HHV-6A and 39 HHV-6B integration remain elusive. Our laboratory has identified that the IE1 protein of 3 40 HHV-6A and HHV-6B target the telomeres. Moreover, we have shown that IE1 associates 41 with a cellular protein, PML, that is responsible for the regulation of important cellular 42 mechanisms such as the life span of cells and DNA repair. Hence, we studied the role of 43 PML in HHV-6 integration. Our study demonstrates that in absence of PML, the HHV-6A 44 and HHV-6B integrate 50-70% less frequently. Thus, our study unveils the first cellular 45 protein involved in HHV-6A and HHV-6 chromosomal integration. 46 47 4 49 Human herpesviruses type 6A and 6B (HHV-6A/B) are members of the betaherpesvirinae 50 that were isolated in the 1980's. In 2013, the International Committee on Taxonomy of 51 Viruses recognized HHV-6A and HHV-6B as distinct viral species (1). HHV-6B is known 52 as the etiologic agent of exanthem subitum, a childhood disease whose symptoms include, 53 fever, occasional skin rash and respiratory distress (2). HHV-6A is much less characterized 54 than HHV-6B. Considering that many HHV-6A/B proteins share 90-95% homology, the

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Collin

Gravel

Kaufer

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…In addition, it has been shown that PML-NBs have role in the repression of HSV-1 infection in the absence of functional ICP0 and they may be involved in regulating lytic and latent infection of HSV-1 (Wang et al, 2012). PML-NB protein has been shown to interact with the EBV protein SM and increase the stability of lytic EBV transcripts (Nicewonger et al, 2004).…”

Section: 8019 Promyelocytic Leukemia Gene Functions and Roles In Tummentioning

confidence: 99%

Promyelocytic Leukemia Gene Functions and Roles in Tumorigenesis

Imani-Saber

Ghafouri‐Fard²

2014

Asian Pacific Journal of Cancer Prevention

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“…PML NBs regulate multiple cellular functions, including antiviral responses (1)(2)(3)(4). Many RNA and DNA viruses, including herpesviruses from all three (alpha, beta, and gamma) subfamilies have correspondingly evolved different mechanisms to modulate PML NBs or PML NB-associated proteins (e.g., Sp100 and Daxx) during both lytic and latent infection (3)(4)(5)(6). For example, herpes simplex virus 1 (HSV-1) ICP0 (7,8), Epstein-Barr virus (EBV) EBNA1 (9), Kaposi's sarcoma-associated herpesvirus (KSHV) LANA2 (10), and murine gammaherpesvirus 68 (MHV68) ORF75c (11,12) target the PML protein for degradation through a proteasome-dependent pathway.…”

mentioning

confidence: 99%

Murine Gammaherpesvirus 68 Encodes a Second PML-Modifying Protein

Sewatanon

Ling

2014

J Virol

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bThe ORF75c tegument protein of murine gammaherpesvirus 68 (MHV68) promotes the degradation of the antiviral promyelocytic leukemia (PML) protein. Surprisingly, MHV68 expressing a degradation-deficient ORF75c replicated in cell culture and in mice similar to the wild-type virus. However, in cells infected with this mutant virus, PML formed novel track-like structures that are induced by ORF61, the viral ribonucleotide reductase large subunit. These findings may explain why ORF75c mutant viruses unable to degrade PML had no demonstrable phenotype after infection. P romyelocytic leukemia (PML) nuclear bodies (NBs) are 0.2-to 1-m nuclear organelles formed by the multimerization of PML proteins (1, 2). PML NBs regulate multiple cellular functions, including antiviral responses (1-4). Many RNA and DNA viruses, including herpesviruses from all three (alpha, beta, and gamma) subfamilies have correspondingly evolved different mechanisms to modulate PML NBs or PML NB-associated proteins (e.g., Sp100 and Daxx) during both lytic and latent infection (3-6). For example, herpes simplex virus 1 (HSV-1) ICP0 (7, 8), Epstein-Barr virus (EBV) EBNA1 (9), Kaposi's sarcoma-associated herpesvirus (KSHV) LANA2 (10), and murine gammaherpesvirus 68 (MHV68) ORF75c (11, 12) target the PML protein for degradation through a proteasome-dependent pathway. Varicella zoster virus (VZV) ORF61 (13), human cytomegalovirus (CMV) IE1 (14), EBV BZLF1 (Zta) (15), and adenovirus type 5 E4 ORF3 (16) disperse PML from nuclear bodies or distort normal PML-NB architecture. Moreover, EBV EBNA-LP (17) and herpesvirus saimiri (HVS) ORF3 (a homolog of gammaherpesvirus ORF75 proteins) (18) relocalize and/ degrade Sp100, respectively, while EBV BNRF1 (19) inactivates Daxx.Investigation of the in vivo consequences of PML-NB disruption during human herpesvirus infection is limited due to the species specificity of most human herpesviruses. Murid herpesvirus 4 (MHV68) is a useful model system for investigating strategies utilized by herpesviruses for establishing long-term chronic infections in an animal because it has a genome organization closely related to human gammaherpesviruses and, like human gammaherpesviruses, it can establish chronic infections and lymphoproliferative diseases in its natural host (20, 21).Previously, we have shown that MHV68 induces the proteasome-dependent degradation of PML via ORF75c, which is a viral tegument protein with homology to the cellular formylglycinamide ribonucleotide amidotransferase (FGARAT) protein (11,12). Surprisingly, acute infection in PML Ϫ/Ϫ mice progressed similarly to that in wild-type (WT) mice. However, MHV68 reactivated with greater efficiency in peritoneal cells from PML Ϫ/Ϫ mice compared to wild-type mice and, in addition, supported higher levels of ongoing persistent infection (22). These data indicate that PML plays a role in establishment and maintenance of latent infection in vivo. To gain more insight into the role of ORF75c and the consequences of PML-NB disruption in vivo, we generated a virus expres...

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The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1

Cited by 20 publications

References 130 publications

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Promyelocytic Leukemia Gene Functions and Roles in Tumorigenesis

Murine Gammaherpesvirus 68 Encodes a Second PML-Modifying Protein

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