WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines

Zhu, Kexin; Wang, Xiang; Ju, Lingao; Zhu, Yuan; Yao, Jie; Wang, Yanyi; Wu, Min; Li, Lianyun

doi:10.4049/jimmunol.1500339

Cited by 17 publications

(18 citation statements)

References 33 publications

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“…Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation ( Claudio et al, 1999 ; Young et al, 2015 ). WDR82 negatively regulates viral replication through mediating TNF receptor associated factor 3 (TRAF3) polyubiquitination status and stability in mitochondria ( Zhu et al, 2015 ). WDR5 promotes the activation of the virus-triggered type I IFN signaling pathway involving epigenetic regulation ( Wang et al, 2010 ; Aitken et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Host Interaction Analysis of PA-N155 and PA-N182 in Chicken Cells Reveals an Essential Role of UBA52 for Replication of H5N1 Avian Influenza Virus

Wang

Liu

et al. 2018

Front. Microbiol.

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PA-N155 and PA-N182 proteins were translated from the 11th and 13th start codon AUG of the RNA polymerase acidic protein (PA) mRNA of H5N1 influenza A virus (IAV), which plays an important role in viral replication. Little is known about the interactions between PA-N155 and PA-N182 and the host proteins. This study investigated the interaction landscape of PA-N155 and PA-N182 of H5N1 IAV in chicken cells while their interacting complexes were captured by immunoprecipitation and analyzed by mass spectrometry. A total of 491 (PA-N155) and 302 (PA-N182) interacting proteins were identified. Gene ontology and pathway enrichment analyses showed that proteins of the two interactomes were enriched in RNA processing, viral processing and protein transport, and proteins related to signaling pathways of proteasome, ribosome, and aminoacy1-tRNA biosynthesis were significantly enriched, suggesting their potential roles in H5N1 IAV infection. Comparative analysis of the interactome of PA, PA-N155, and PA-N182 identified UBA52 as a conserved host factor that interacted with all three viral proteins. UBA52 is a fusion protein consisting of ubiquitin at the N terminus and ribosomal protein L40 at the C terminus. Knockdown of UBA52 significantly decreased the titer of H5N1 IAV in chicken cells and was accompanied with attenuated production of proinflammatory cytokines. Our analyses of the influenza–host protein interactomes identified UBA52 as a PA interaction protein for virus replication.

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Section: Discussionmentioning

confidence: 99%

Host Interaction Analysis of PA-N155 and PA-N182 in Chicken Cells Reveals an Essential Role of UBA52 for Replication of H5N1 Avian Influenza Virus

Wang

Liu

et al. 2018

Front. Microbiol.

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“…The Journal of Immunology regulating TRAF3 polyubiquitination (24). A SET domaincontaining protein, TTLL12, is identified from the screen.…”

Section: The Inhibition Of Sev-induced Antiviral Gene Expression By Tmentioning

confidence: 99%

“…Recently, a putative link between protein methylation and VISA/MAVS-dependent IFNB1 expression has been suggested. WD repeat domain 5 (WDR5) and WD repeat domain 82 (WDR82), two subunits of histone H3K4 methyltransferase complexes, were reported to regulate the virustriggered type I IFN signaling (22)(23)(24). WDR5 is a common subunit of six histone H3K4 methyltransferase complexes, namely SET domain containing 1A/B (SETD1A/B) and myeloid/lymphoid or mixed-lineage leukemia 1-4 (22,(25)(26)(27); and WDR82 is a unique subunit of SETD1A/B complexes (28,29).…”

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confidence: 99%

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TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS

Ju¹,

Zhu²,

Lei³

et al. 2017

The Journal of Immunology

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Upon virus infection, host cells use retinoic-acid-inducible geneI I (RIG-I)-like receptors to recognize viral RNA and activate type I IFN expression. To investigate the role of protein methylation in the antiviral signaling pathway, we screened all the SET domain-containing proteins and identified TTLL12 as a negative regulator of RIG-I signaling. TTLL12 contains SET and TTL domains, which are predicted to have lysine methyltransferase and tubulin tyrosine ligase activities, respectively. Exogenous expression of TTLL12 represses IFN-β expression induced by Sendai virus. TTLL12 deficiency by RNA interference and CRISPR-gRNA techniques increases the induced IFN-β expression and inhibits virus replication in the cell. The global gene expression profiling indicated that TTLL12 specifically inhibits the expression of the downstream genes of innate immunity pathways. Cell fractionation and fluorescent staining indicated that TTLL12 is localized in the cytosol. The mutagenesis study suggested that TTLL12's ability to repress the RIG-I pathway is probably not dependent on protein modifications. Instead, TTLL12 directly interacts with virus-induced signaling adaptor (VISA), TBK1, and IKKε, and inhibits the interactions of VISA with other signaling molecules. Taken together, our findings demonstrate TTLL12 as a negative regulator of RNA-virus-induced type I IFN expression by inhibiting the interaction of VISA with other proteins.

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“…For instance, inhibition of histone methyltransferase G9a induces Akt phosphorylation in glioma cells (34). The H3K4 methyltransferase WDR82 negatively regulates cellular antiviral response by mediating TNFR-associated factor (TRAF)3 polyubiquitination in multiple cell lines (35). However, whether the phosphorylation and ubiquitination of STAT3 are modulated by epigenetic proteins is not known.…”

mentioning

confidence: 99%

Epigenetic Component p66a Modulates Myeloid-Derived Suppressor Cells by Modifying STAT3

Xin

Zhang

et al. 2017

The Journal of Immunology

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STAT3 plays a critical role in myeloid-derived suppressor cell (MDSC) accumulation and activation. Most studies have probed underlying mechanisms of STAT3 activation. However, epigenetic events involved in STAT3 activation are poorly understood. In this study, we identified several epigenetic-associated proteins such as p66a (Gatad2a), a novel protein transcriptional repressor that might interact with STAT3 in functional MDSCs, by using immunoprecipitation and mass spectrometry. p66a could regulate the phosphorylation and ubiquitination of STAT3. Silencing p66a promoted not only phosphorylation but also K63 ubiquitination of STAT3 in the activated MDSCs. Interestingly, p66a expression was significantly suppressed by IL-6 both in vitro and in vivo during MDSC activation, suggesting that p66a is involved in IL-6-mediated differentiation of MDSCs. Indeed, silencing p66a could promote MDSC accumulation, differentiation, and activation. Tumors in mice injected with p66a small interfering RNA-transfected MDSCs also grew faster, whereas tumors in mice injected with p66a-transfected MDSCs were smaller as compared with the control. Thus, our data demonstrate that p66a may physically interact with STAT3 to suppress its activity through posttranslational modification, which reveals a novel regulatory mechanism controlling STAT3 activation during myeloid cell differentiation.

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WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines

Cited by 17 publications

References 33 publications

Host Interaction Analysis of PA-N155 and PA-N182 in Chicken Cells Reveals an Essential Role of UBA52 for Replication of H5N1 Avian Influenza Virus

Host Interaction Analysis of PA-N155 and PA-N182 in Chicken Cells Reveals an Essential Role of UBA52 for Replication of H5N1 Avian Influenza Virus

TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS

Epigenetic Component p66a Modulates Myeloid-Derived Suppressor Cells by Modifying STAT3

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