Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus

Kim, Young-Eui; Ahn, Jin-Hyun

doi:10.1371/journal.ppat.1004785

Cited by 72 publications

(113 citation statements)

References 58 publications

(70 reference statements)

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“…7). This finding confirms and complements the results of a study by Kim and Ahn on the role of PML in type I interferon response, which was published while this paper was in preparation (59). By using PML knockdown cells, they demonstrated that PML is required for an efficient accumulation of STAT proteins and their phosphorylated forms.…”

Section: Discussionsupporting

confidence: 88%

“…6B and 8C). Thus, these results complement the experiments of Kim and Ahn (59), which analyzed the consequences of deletions within the PML-binding domain IE1 CORE or the STAT interaction region on the capacity of IE1 to inhibit type I IFN signaling. They suggested a requirement of both PML binding and STAT binding for an efficient inhibition of the interferon response by IE1 and proposed sequestration of PML/STAT complexes as a mechanistic basis.…”

Section: Discussionsupporting

confidence: 79%

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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

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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...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 79%

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

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“…It has been demonstrated that HDAC1 specifically coactivates the promyelocytic leukemia zinc finger and promyelocytic leukemia proteins that are involved in type I IFN-mediated innate immune response and subsequent expression of ISGs like viperin (32,37). The above data demonstrated that class I and class II HDAC activity is required for the IAV-induced host type I IFN-mediated antiviral response and the expression of ISGs, including viperin.…”

Section: Fig 3 the Overexpression Of Hdac1 Inhibits Iav Infection (Amentioning

confidence: 81%

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Nagesh

Husain

2016

J Virol

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Viruses dysregulate the host factors that inhibit virus infection. Here, we demonstrate that human enzyme, histone deacetylase 1 (HDAC1) is a new class of host factor that inhibits influenza A virus (IAV) infection, and IAV dysregulates HDAC1 to efficiently replicate in epithelial cells. A time-dependent decrease in HDAC1 polypeptide level was observed in IAV-infected cells, reducing to <50% by 24 h of infection. A further depletion (97%) of HDAC1 expression by RNA interference increased the IAV growth kinetics, increasing it by >3-fold by 24 h and by >6-fold by 48 h of infection. Conversely, overexpression of HDAC1 decreased the IAV infection by >2-fold. Likewise, a time-dependent decrease in HDAC1 activity, albeit with slightly different kinetics to HDAC1 polypeptide reduction, was observed in infected cells. Nevertheless, a further inhibition of deacetylase activity increased IAV infection in a dose-dependent manner. HDAC1 is an important host deacetylase and, in addition to its role as a transcription repressor, HDAC1 has been lately described as a coactivator of type I interferon response. Consistent with this property, we found that inhibition of deacetylase activity either decreased or abolished the phosphorylation of signal transducer and activator of transcription I (STAT1) and expression of interferon-stimulated genes, IFITM3, ISG15, and viperin in IAV-infected cells. Furthermore, the knockdown of HDAC1 expression in infected cells decreased viperin expression by 58% and, conversely, the overexpression of HDAC1 increased it by 55%, indicating that HDAC1 is a component of IAV-induced host type I interferon antiviral response. IMPORTANCEInfluenza A virus (IAV) continues to significantly impact global public health by causing regular seasonal epidemics, occasional pandemics, and zoonotic outbreaks. IAV is among the successful human viral pathogens that has evolved various strategies to evade host defenses, prevent the development of a universal vaccine, and acquire antiviral drug resistance. A comprehensive knowledge of IAV-host interactions is needed to develop a novel and alternative anti-IAV strategy. Host produces a variety of factors that are able to fight IAV infection by employing various mechanisms. However, the full repertoire of anti-IAV host factors and their antiviral mechanisms has yet to be identified. We have identified here a new host factor, histone deacetylase 1 (HDAC1) that inhibits IAV infection. We demonstrate that HDAC1 is a component of host innate antiviral response against IAV, and IAV undermines HDAC1 to limit its role in antiviral response. Influenza A virus (IAV), a prototypic member of family Orthomyxoviridae, has been a successful human respiratory pathogen. IAV has prevented the development of a universal vaccine so far and rendered the currently approved anti-influenza virus drugs almost ineffective. A unique genetic make-up comprising of a segmented RNA genome and a broad host range of humans, birds, pigs, dogs, cats, horses, seals, and bats allows the regular emer...

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“…Several previous reports have highlighted a complex role of the IFN pathway in response to HCMV. The activity of the promyeolcytic leukemia protein, a regulator of type I IFN response, is counteracted by HCMV-encoded immediate early 1 protein (IE1) (6). A cytoplasmic dsDNA sensor, ZBP1, activates IRF3 on infection, and its overexpression inhibits HCMV replication (7).…”

Section: Ripk2mentioning

confidence: 99%

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Fan

Roy

Mukhopadhyay

et al. 2016

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

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Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-β. Mouse CMV was also inhibited through NOD1 activation. NOD1 knockdown (KD) or inhibition of its activity with small molecule ML130 enhanced HCMV replication in vitro. NOD1 mutations displayed differential effects on HCMV replication and antiviral responses. In cells overexpressing the E56K mutation in the caspase activation and recruitment domain, virus replication was enhanced, but in cells overexpressing the E266K mutation in the nucleotidebinding domain or the wild-type NOD1, HCMV was inhibited, changes that correlated with IFN-β expression. The interaction of NOD1 and RIPK2 determined the outcome of virus replication, as evidenced by enhanced virus growth in NOD1 E56K mutant cells (which failed to interact with RIPK2). NOD1 activities were executed through IFN-β, given that IFN-β KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKα-dependent and correlated with nuclear translocation and phosphorylation of IRF3. Finally, NOD1 polymorphisms were significantly associated with the risk of HCMV infection in women who were infected with HCMV during participation in a glycoprotein B vaccine trial. Collectively, our data indicate a role for NOD1 in HCMV control via RIPK2-IKKα-IRF3 and suggest that its polymorphisms predict the risk of infection.H uman cytomegalovirus (HCMV), a member of the herpesvirus family, induces complex innate immune responses (1, 2). Despite this effective and multifaceted induction, HCMV has developed strategies to counteract its recognition (3), allowing for its productive replication and the establishment of latency. Identification and characterization of HCMV-induced innate immune responses and resulting signaling pathways may provide novel strategies for its control.Mounting evidence indicates that HCMV sensing is an intricate process involving activities of membrane, cytoplasmic, and nuclear receptors. Several HCMV-encoded proteins directly activate innate immune response molecules; the glycoprotein B (gB) binds to and activates TLR2 (4), and pp65 interacts with IFI16 (5). Other viral proteins, dsDNA, or dsRNA are likely to activate or inhibit host innate response molecules. Several previous reports have highlighted a complex role of the IFN pathway in response to HCMV. The activity of the promyeolcytic leukemia protein, a regulator of type I IFN response, is counteracted by HCMV-encoded immediate early 1 protein (IE1) (6). A cytoplasmic dsDNA sensor, ZBP1, activates IRF3 on infection, and its overexpression inhibits HCMV replication (7). IFN-inducible protein IFI16 modestly in...

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Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus

Cited by 72 publications

References 58 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

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

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