PML nuclear bodies contribute to the basal expression of the mTOR inhibitor DDIT4

While interferon restricts SARS-CoV-2 replication in cell culture, only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identified DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 replication in human cells. Basal expression of DAXX was sufficient to limit the replication of the virus, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites of viral replication and led to its degradation. Together, these results demonstrate that DAXX is a potent restriction factor for SARS-CoV-2 and that the virus has evolved a mechanism to counteract its action.

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Faculty Opinions recommendation of Disruption of PML nuclear bodies is mediated by ORF61 SUMO-interacting motifs and required for varicella-zoster virus pathogenesis in skin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13038957.14357055 ◽

2011 ◽

Author(s):

David Leib

Keyword(s):

Varicella Zoster Virus ◽

Nuclear Bodies ◽

Varicella Zoster ◽

Pml Nuclear Bodies

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Hepatitis C-associated liver carcinogenesis: Role of PML nuclear bodies

World Journal of Gastroenterology ◽

10.3748/wjg.v20.i35.12367 ◽

2014 ◽

Vol 20 (35) ◽

pp. 12367 ◽

Cited By ~ 8

Author(s):

Kerstin Herzer

Keyword(s):

Hepatitis C ◽

Nuclear Bodies ◽

Liver Carcinogenesis ◽

Pml Nuclear Bodies

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Proximity to PML Nuclear Bodies Regulates HIV-1 Latency in CD4+ T Cells

Cell Host & Microbe ◽

10.1016/j.chom.2013.05.006 ◽

2013 ◽

Vol 13 (6) ◽

pp. 665-677 ◽

Cited By ~ 68

Author(s):

Marina Lusic ◽

Bruna Marini ◽

Hashim Ali ◽

Bojana Lucic ◽

Roberto Luzzati ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Nuclear Bodies ◽

Pml Nuclear Bodies ◽

Hiv 1

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Correlative FIB-SEM tomography in herpesvirus research: PML nuclear bodies restrict herpesvirus infection by entrapment of newly assembled viral capsids

10.22443/rms.emc2020.831 ◽

2021 ◽

Author(s):

Clarissa Read (Villinger) ◽

Keyword(s):

Nuclear Bodies ◽

Herpesvirus Infection ◽

Viral Capsids ◽

Pml Nuclear Bodies

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Complex regulation and nuclear localization of JRK protein

Biochemical Society Transactions ◽

10.1042/bst0320920 ◽

2004 ◽

Vol 32 (6) ◽

pp. 920-923 ◽

Cited By ~ 3

Author(s):

R. Waldron ◽

T. Moore

Keyword(s):

Cellular Localization ◽

Fluorescent Protein ◽

Binding Protein ◽

Distinct Pattern ◽

Nuclear Bodies ◽

Null Mouse ◽

Fluorescence Confocal Microscopy ◽

Pml Nuclear Bodies ◽

Generalized Epilepsy ◽

Green Fluorescent

The mouse jerky gene and its human orthologue, JRK/JH8, encode a putative DNA-binding protein with homology to the CENP-B (centromere-binding protein B). Disruption of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy. In addition (and similar to a cenp-b null mouse) jerky null mice exhibit postnatal weight loss and reduced fertility. Using fluorescence confocal microscopy, the cellular localization of a JRK–GFP fusion (where GFP stands for green fluorescent protein) was investigated in HeLa cells. JRK–GFP has a dynamic expression pattern in the interphase nucleus, localizing in a small number of punctate nuclear foci and in the nucleolus. The JRK–GFP foci number changes during the cell cycle, but a distinct pattern of three JRK–GFP foci is observed at G2. The endogenous protein behaves in a similar manner to the GFP-fusion protein. JRK–GFP was found to co-localize with CREST antigens (which recognize the centromere-binding proteins, CENP-A, -B and -C) through S and G2 phases of interphase and co-localized completely with a subset of PML nuclear bodies at G2. We speculate that JRK protein associates with a specific chromosomal centromeric locus in G2, where it associates fully with PML bodies. Research is underway to identify this locus.

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Adenovirus E1B 55-Kilodalton Protein Is a p53-SUMO1 E3 Ligase That Represses p53 and Stimulates Its Nuclear Export through Interactions with Promyelocytic Leukemia Nuclear Bodies

Journal of Virology ◽

10.1128/jvi.01442-10 ◽

2010 ◽

Vol 84 (23) ◽

pp. 12210-12225 ◽

Cited By ~ 54

Author(s):

Mario A. Pennella ◽

Yue Liu ◽

Jennifer L. Woo ◽

Chongwoo A. Kim ◽

Arnold J. Berk

Keyword(s):

Nuclear Export ◽

P53 Mutation ◽

Promyelocytic Leukemia ◽

Nuclear Bodies ◽

Live Cells ◽

High Concentration ◽

Sumoylation Site ◽

Pml Nuclear Bodies ◽

Induced Apoptosis

ABSTRACT Oncogenic transformation by adenovirus E1A and E1B-55K requires E1B-55K inhibition of p53 activity to prevent E1A-induced apoptosis. During viral infection, E1B-55K and E4orf6 substitute for the substrate-binding subunits of the host cell cullin 5 class of ubiquitin ligases, resulting in p53 polyubiquitinylation and proteasomal degradation. Here we show that E1B-55K alone also functions as an E3 SUMO1-p53 ligase. Fluorescence microscopy studies showed that E1B-55K alone, in the absence of other viral proteins, causes p53 to colocalize with E1B-55K in promyelocytic leukemia (PML) nuclear bodies, nuclear domains with a high concentration of sumoylated proteins. Photobleaching experiments with live cells revealed that E1B-55K tethering of p53 in PML nuclear bodies decreases the in vivo nuclear mobility of p53 nearly 2 orders of magnitude. E1B-55K-induced p53 sumoylation contributes to maximal inhibition of p53 function since mutation of the major p53 sumoylation site decreases E1B-55K-induced p53 sumoylation, tethering in PML nuclear bodies, and E1B-55K inhibition of p53 activity. Mutation of the E1B-55K sumoylation site greatly inhibits E1B-55K association with PML nuclear bodies and the p53 nuclear export to cytoplasmic aggresomes observed in E1A-E1B-transformed cells. Purified E1B-55K and p53 form high-molecular-weight complexes potentially through the formation of a network of E1B-55K dimers bound to the N termini of p53 tetramers. In support of this model, a p53 mutation that prevents tetramer formation greatly reduces E1B-55K-induced tethering in PML nuclear bodies and p53 nuclear export. These data indicate that E1B-55K's association with PML nuclear bodies inactivates p53 by first sequestering it in PML nuclear bodies and then greatly facilitating its nuclear export.

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