PML promotes MHC class II gene expression by stabilizing the class II transactivator

Ulbricht, Tobias; Alzrigat, Mohammad; Horch, Almut; Reuter, Nina; Mikecz, Anna von; Steimle, Viktor; Schmitt, Eberhard; Krämer, Oliver H.; Stamminger, Thomas; Hemmerich, Peter

doi:10.1083/jcb.201112015

Cited by 57 publications

(64 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent evidence suggested a positive effect of PML on transcription of IFN-␥-stimulated genes and an involvement of one specific PML isoform in IFN-␤ production (44)(45)(46); however, the exact role of PML is far from being understood. To further characterize the influence of PML on interferon signaling, we measured ISG induction in HFFs with an shRNA-mediated depletion of PML (siPML) in comparison to that observed in control cells (siC).…”

Section: Effects Of Ie1 Mutants Ie1-l174p and Ie1 1-382 On The Inhibimentioning

confidence: 99%

“…This intermediate effect may arise from the low levels of IE1-L174P during infection. However, since PML recently emerged as a positive regulator of interferon signaling (44)(45)(46), it is also possible that the loss of PML binding caused by L174P mutation accounts for the inefficient suppression of the interferon response.…”

Section: Effects Of Ie1 Mutants Ie1-l174p and Ie1 1-382 On The Inhibimentioning

confidence: 99%

“…While one study demonstrated an effect of all nuclear PML isoforms on IFN-␥-induced STAT1 phosphorylation and DNA binding (44), a subsequent study reported that a specific PML isoform, PML II, recruits the major histocompatibility complex class II (MHC-II) transactivator (CIITA) to ND10, resulting in stabilization of CIITA and enhancement of IFN-␥-induced MHC-II expression (45). Furthermore, a contribution of PML isoform IV to IFN-␤ production was suggested (46).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Characterization of Recombinant Human Cytomegaloviruses Encoding IE1 Mutants L174P and 1-382 Reveals that Viral Targeting of PML Bodies Perturbs both Intrinsic and Innate Immune Responses

Scherer

Otto

Stump

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

PML is the organizer of cellular structures termed nuclear domain 10 (ND10) or PML-nuclear bodies (PML-NBs) that act as key mediators of intrinsic immunity against human cytomegalovirus (HCMV) and other viruses. The antiviral function of ND10 is antagonized by viral regulatory proteins such as the immediate early protein IE1 of HCMV. IE1 interacts with PML through its globular core domain (IE1 CORE ) and induces ND10 disruption in order to initiate lytic HCMV infection. Here, we investigate the consequences of a point mutation (L174P) in IE1 CORE , which was shown to abrogate the interaction with PML, for lytic HCMV infection. We found that a recombinant HCMV encoding IE1-L174P displays a severe growth defect similar to that of an IE1 deletion virus. Bioinformatic modeling based on the crystal structure of IE1 CORE suggested that insertion of proline into the highly alpha-helical domain severely affects its structural integrity. Consistently, L174P mutation abrogates the functionality of IE1 CORE and results in degradation of the IE1 protein during infection. In addition, our data provide evidence that IE1 CORE as expressed by a recombinant HCMV encoding IE1 1-382 not only is required to antagonize PML-mediated intrinsic immunity but also affects a recently described function of PML in innate immune signaling. We demonstrate a coregulatory role of PML in type I and type II interferon-induced gene expression and provide evidence that upregulation of interferon-induced genes is inhibited by IE1 CORE . In conclusion, our data suggest that targeting PML by viral regulatory proteins represents a strategy to antagonize both intrinsic and innate immune mechanisms. IMPORTANCEPML nuclear bodies (PML-NBs), which represent nuclear multiprotein complexes consisting of PML and additional proteins, represent important cellular structures that mediate intrinsic resistance against many viruses, including human cytomegalovirus (HCMV). During HCMV infection, the major immediate early protein IE1 binds to PML via a central globular domain (IE1 CORE ), and we have shown previously that this is sufficient to antagonize intrinsic immunity. Here, we demonstrate that modification of PML by IE1 CORE not only abrogates intrinsic defense mechanisms but also attenuates the interferon response during infection. Our data show that PML plays a novel coregulatory role in type I as well as type II interferon-induced gene expression, which is antagonized by IE1 CORE . Importantly, our finding supports the view that targeting of PML-NBs by viral regulatory proteins has evolved as a strategy to inhibit both intrinsic and innate immune defense mechanisms. H uman cytomegalovirus (HCMV), a member of the ␤-subgroup of herpesviruses, is a widespread human pathogen of high clinical relevance that can cause life-threatening diseases in newborns and people with compromised immune system such as AIDS, transplantation, or malignancy patients. The lytic replication cycle of HCMV is characterized by three sequential phases of viral gene expression, te...

show abstract

Section: Effects Of Ie1 Mutants Ie1-l174p and Ie1 1-382 On The Inhibimentioning

confidence: 99%

Section: Effects Of Ie1 Mutants Ie1-l174p and Ie1 1-382 On The Inhibimentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Recombinant Human Cytomegaloviruses Encoding IE1 Mutants L174P and 1-382 Reveals that Viral Targeting of PML Bodies Perturbs both Intrinsic and Innate Immune Responses

Scherer

Otto

Stump

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The combination of genomic sequences and genome-wide expression studies have revealed another form of nonrandom gene distribution, termed tandem gene arrays (TGAs), which represent contiguous stretches of gene loci that display differential regulation during cellular development and/or function (4,5). Importantly, gene clusters and TGAs also demonstrate expression-dependent nuclear localization patterns (6-9); therefore, gene loci are both deterministically arrayed along chromosomes and positioned within the nucleus (10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

Neems

Garza-Gongora

Smith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The linear distribution of genes across chromosomes and the spatial localization of genes within the nucleus are related to their transcriptional regulation. The mechanistic consequences of linear gene order, and how it may relate to the functional output of genome organization, remain to be fully resolved, however. Here we tested the relationship between linear and 3D organization of gene regulation during myogenesis. Our analysis has identified a subset of topologically associated domains (TADs) that are significantly enriched for muscle-specific genes. These lineage-enriched TADs demonstrate an expression-dependent pattern of nuclear organization that influences the positioning of adjacent nonenriched TADs. Therefore, lineageenriched TADs inform cell-specific genome organization during myogenesis. The reduction of allelic spatial distance of one of these domains, which contains Myogenin, correlates with reduced transcriptional variability, identifying a potential role for lineage-specific nuclear topology. Using a fusion-based strategy to decouple mitosis and myotube formation, we demonstrate that the cell-specific topology of syncytial nuclei is dependent on cell division. We propose that the effects of linear and spatial organization of gene loci on gene regulation are linked through TAD architecture, and that mitosis is critical for establishing nuclear topologies during cellular differentiation.cell differentiation | gene regulation | nuclear organization | transcriptional noise | 3D image analysis

show abstract

“…2E), the possibility that an IRIF/PML body association occurs randomly in the nucleus could not be fully excluded. We therefore employed a self-developed algorithm (48) to calculate the theoretical probability of association events between IRIF and PML bodies. This required determination of the number and volume of PML bodies and IRIF and the nuclear volume at several time points after irradiation (data not shown).…”

Section: Resultsmentioning

confidence: 99%

The Tumor Suppressor PML Specifically Accumulates at RPA/Rad51-Containing DNA Damage Repair Foci but Is Nonessential for DNA Damage-Induced Fibroblast Senescence

Münch

Weidtkamp‐Peters

Klement

et al. 2014

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

The PML tumor suppressor has been functionally implicated in DNA damage response and cellular senescence. Direct evidence for such a role based on PML knockdown or knockout approaches is still lacking. We have therefore analyzed the irradiationinduced DNA damage response and cellular senescence in human and mouse fibroblasts lacking PML. Our data show that PML nuclear bodies (NBs) nonrandomly associate with persistent DNA damage foci in unperturbed human skin and in high-doseirradiated cell culture systems. PML bodies do not associate with transient ␥H2AX foci after low-dose gamma irradiation. Superresolution microscopy reveals that all PML bodies within a nucleus are engaged at Rad51-and RPA-containing repair foci during ongoing DNA repair. The lack of PML (i) does not majorly affect the DNA damage response, (ii) does not alter the efficiency of senescence induction after DNA damage, and (iii) does not affect the proliferative potential of primary mouse embryonic fibroblasts during serial passaging. Thus, while PML NBs specifically accumulate at Rad51/RPA-containing lesions and senescencederived persistent DNA damage foci, they are not essential for DNA damage-induced and replicative senescence of human and murine fibroblasts.

show abstract

PML promotes MHC class II gene expression by stabilizing the class II transactivator

Abstract: Promyelocytic leukemia (PML) protein binds to and stabilizes CIITA at PML nuclear bodies, which promotes expression of the MHC class II gene locus in response to interferon-γ exposure.

Cited by 57 publications

References 73 publications

Characterization of Recombinant Human Cytomegaloviruses Encoding IE1 Mutants L174P and 1-382 Reveals that Viral Targeting of PML Bodies Perturbs both Intrinsic and Innate Immune Responses

Characterization of Recombinant Human Cytomegaloviruses Encoding IE1 Mutants L174P and 1-382 Reveals that Viral Targeting of PML Bodies Perturbs both Intrinsic and Innate Immune Responses

Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

The Tumor Suppressor PML Specifically Accumulates at RPA/Rad51-Containing DNA Damage Repair Foci but Is Nonessential for DNA Damage-Induced Fibroblast Senescence

Contact Info

Product

Resources

About