PML Bodies in Mitosis

Lång, Anna; Lång, Emma; Bøe, Stig Ove

doi:10.3390/cells8080893

Cited by 24 publications

(20 citation statements)

References 146 publications

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“…ICP0 was initially identified as an E3 Ub ligase by virtue of its ability to localize to and disrupt PML-NBs ( Everett, 2000 ; Maul et al, 1993 ; Maul and Everett, 1994 ; Everett and Maul, 1994 ; Everett et al, 1998 ; Chelbi-Alix and de The, 1999 ). PML-NBs are highly dynamic nuclear substructures composed of more than 70 proteins that respond to a variety of stimuli, including heat shock, cytokine signalling, and virus infection ( Lang et al, 2010 ; Van Damme et al, 2010 ; Hoischen et al, 2018 ; Lang et al, 2019 ; Bernardi and Pandolfi, 2007 ; Maul et al, 1995 ). Infecting HSV-1 genomes are rapidly entrapped by PML-NBs upon nuclear entry ( Alandijany et al, 2018 ; Dembowski and Deluca, 2017 ), a host response that can lead to viral genome silencing as a component of the intrinsic antiviral immune response (discussed below) ( Alandijany et al, 2018 ; Everett et al, 2006 ; Everett et al, 2008a ; Glass and Everett, 2013 ; Cabral et al, 2018 ).…”

Section: Icp0-mediated Degradation Of Pml-nbs and Sumoylated Host Promentioning

confidence: 99%

The HSV-1 ubiquitin ligase ICP0: Modifying the cellular proteome to promote infection

et al. 2020

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Highlights ICP0 is a viral E3 ubiquitin ligase that promotes HSV-1 infection. ICP0 interacts with multiple component proteins of the ubiquitin pathway. ICP0 disrupts multiple cellular processes activated in response to infection ICP0 remodels the SUMO proteome to counteract host immune defences to infection. ICP0 is an attractive drug target for the development of antiviral HSV-1 therapeutics.

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Section: Icp0-mediated Degradation Of Pml-nbs and Sumoylated Host Promentioning

confidence: 99%

The HSV-1 ubiquitin ligase ICP0: Modifying the cellular proteome to promote infection

et al. 2020

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“…Conversely, no co-staining at condensed chromatin was observed between PML and IE1 mutants highly defective in PML body targeting (IE1cc134-136, cc161-165, cc172-176, cc258-263, cc286-292, cc307-310, cc318-319). In the presence of these IE1 mutants, or in the absence of IE1 proteins, PML formed complexes referred to as MAPPs across the mitotic cells (reviewed in [96,97]). These complexes were also observed in cells expressing IE2, but not when wild-type IE1 was expressed.…”

Section: Plos Pathogensmentioning

confidence: 99%

Revisiting promyelocytic leukemia protein targeting by human cytomegalovirus immediate-early protein 1

et al. 2020

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Promyelocytic leukemia (PML) bodies are nuclear organelles implicated in intrinsic and innate antiviral defense. The eponymous PML proteins, central to the self-organization of PML bodies, and other restriction factors found in these organelles are common targets of viral antagonism. The 72-kDa immediate-early protein 1 (IE1) is the principal antagonist of PML bodies encoded by the human cytomegalovirus (hCMV). IE1 is believed to disrupt PML bodies by inhibiting PML SUMOylation, while PML was proposed to act as an E3 ligase for IE1 SUMOylation. PML targeting by IE1 is considered to be crucial for hCMV replication at low multiplicities of infection, in part via counteracting antiviral gene induction linked to the cellular interferon (IFN) response. However, current concepts of IE1-PML interaction are largely derived from mutant IE1 proteins known or predicted to be metabolically unstable and globally misfolded. We performed systematic clustered charge-to-alanine scanning mutagenesis and identified a stable IE1 mutant protein (IE1cc172-176) with wild-type characteristics except for neither interacting with PML proteins nor inhibiting PML SUMOylation. Consequently, IE1cc172-176 does not associate with PML bodies and is selectively impaired for disrupting these organelles. Surprisingly, functional analysis of IE1cc172-176 revealed that the protein is hypermodified by mixed SUMO chains and that IE1 SUMOylation depends on nucleosome rather than PML binding. Furthermore, a mutant hCMV expressing IE1cc172-176 was only slightly attenuated compared to an IE1-null virus even at low multiplicities of infection. Finally, hCMV-induced expression of cytokine and IFN-stimulated genes turned out to be reduced rather than increased in the presence of IE1cc172-176 relative to wild-type IE1. Our findings challenge present views on the relationship of IE1 with PML and the role of PML in hCMV replication. This study also provides initial evidence for

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“…The human-and primate-specific L1 ASPs reportedly drive ORF0-containing transcripts, whose encoded protein, ORF0p, is predominantly nuclear and localizes in close proximity to PML-NBs 12 . PML-NBs are implicated in various biological processes, including mitosis 27 . Because our cell cycle analysis demonstrated that L1 ASP activation shortens the duration of the S-G2 phase, L1 ASP activation may accelerate mitosis through PML-NBs and L1 ASP-driven ORF0p, thereby supporting efficient cell growth.…”

Section: Discussionmentioning

confidence: 99%

Effects of activation of the LINE-1 antisense promoter on the growth of cultured cells

Honda

Nishimura

Teng

et al. 2020

Sci Rep

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Long interspersed element 1 (LINE-1, or L1) is a retrotransposon that constitutes ~ 17% of the human genome. Although ~ 6000 full-length L1s spread throughout the human genome, their biological significance remains undetermined. The L1 5′ untranslated region has bidirectional promoter activity with a sense promoter driving L1 mRNA production and an antisense promoter (ASP) driving the production of L1-gene chimeric RNAs. Here, we stimulated L1 ASP activity using CRISPR-Cas9 technology to evaluate its biological impacts. Activation of the L1 ASP upregulated the expression of L1 ASP-driven ORF0 and enhanced cell growth. Furthermore, the exogenous expression of ORF0 also enhanced cell growth. These results indicate that activation of L1 ASP activity fuels cell growth at least through ORF0 expression. To our knowledge, this is the first report demonstrating the role of the L1 ASP in a biological context. Considering that L1 sequences are desilenced in various tumor cells, our results indicate that activation of the L1 ASP may be a cause of tumor growth; therefore, interfering with L1 ASP activity may be a potential strategy to suppress the growth.

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PML Bodies in Mitosis

Cited by 24 publications

References 146 publications

The HSV-1 ubiquitin ligase ICP0: Modifying the cellular proteome to promote infection

The HSV-1 ubiquitin ligase ICP0: Modifying the cellular proteome to promote infection

Revisiting promyelocytic leukemia protein targeting by human cytomegalovirus immediate-early protein 1

Effects of activation of the LINE-1 antisense promoter on the growth of cultured cells

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