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ATP1B3 Protein Modulates the Restriction of HIV-1 Production and Nuclear Factor ? Light Chain Enhancer of Activated B Cells (NF-?B) Activation by BST-2.

ABSTRACT: Here, we identify ATP1B3 and fibrillin-1 as novel BST-2-binding proteins. ATP1B3 depletion in HeLa cells (BST-2-positive cells), but not 293T cells (BST-2-negative cells), induced the restriction of HIV-1 production in a BST-2-dependent manner. In contrast, fibrillin-1 knockdown reduced HIV-1 production in 293T and HeLa cells in a BST-2-independent manner. Moreover, NF-?B activation was enhanced by siATP1B3 treatment in HIV-1- and HIV-1?Vpu-infected HeLa cells. In addition, ATP1B3 silencing induced high level BST-2 expression on the surface of HeLa cells. These results indicate that ATP1B3 is a co-factor that accelerates BST-2 degradation and reduces BST-2-mediated restriction of HIV-1 production and NF-?B activation.

SUBMITTER: Nishitsuji H

PROVIDER: S-EPMC4813497 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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ATP1B3 Protein Modulates the Restriction of HIV-1 Production and Nuclear Factor κ Light Chain Enhancer of Activated B Cells (NF-κB) Activation by BST-2.

Nishitsuji Hironori H Sugiyama Ryuichi R Abe Makoto M Takaku Hiroshi H

The Journal of biological chemistry 20151222 9

Here, we identify ATP1B3 and fibrillin-1 as novel BST-2-binding proteins. ATP1B3 depletion in HeLa cells (BST-2-positive cells), but not 293T cells (BST-2-negative cells), induced the restriction of HIV-1 production in a BST-2-dependent manner. In contrast, fibrillin-1 knockdown reduced HIV-1 production in 293T and HeLa cells in a BST-2-independent manner. Moreover, NF-κB activation was enhanced by siATP1B3 treatment in HIV-1- and HIV-1ΔVpu-infected HeLa cells. In addition, ATP1B3 silencing indu ...[more]

PMID: 26694617

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Project description:Inflammatory bowel diseases (IBD), encompassing both Crohn Disease (CD) and ulcerative colitis (UC) are globally prevalent diseases, impacting children of all ages. The hallmark of IBD is a perturbed immune system that leads to continuous inflammation in the gut and challenges optimal treatment. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-??), a nuclear transcription factor, plays a major role in gut homeostasis and contributes significantly toward a balanced, homeostatic immune system. Dysregulation in the NF-?? pathway and factors that regulate it lead to a state of uncontrolled inflammation and altered immunity, as typically observed in IBD. Levels of proinflammatory cytokines that are regulated through NF-?? are increased in both CD and UC. Genes known to activate NF-??, such as, Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Interleukin 23 (IL-23), are associated with IBD. Factors involved in inhibition of NF-??, such as A20 and TOLLIP, are also affected in IBD, resulting in failed inflammation suppression/regulation. NOD-2 and A20 have specifically been found to be strongly associated with pediatric IBD. Gut commensals are known to exert anti-inflammatory activities toward NF-?? and can have a potential role in attenuating inflammation that likely occurs due to microbial dysbiosis in IBD. Failure to terminate/downregulate NF-?? signaling results in chronic inflammation in IBD. Well-regulated control of inflammation in children with IBD can help better control the disease and suppress immune responses. Better understanding of factors that control NF-?? can potentially lead toward discovering targeted therapeutic interventions for IBD. Suppression of NF-?? can be achieved through many modalities including anti-sense oligonucleotides (ASOs), siRNA (small interfering RNA), factors regulating NF-??, and microbes. This review focuses on the role of NF-??, especially in pediatric IBD, and potential therapeutic venues for attenuating NF-??-induced inflammation.

Project description:BackgroundExpression of kappa gene is under the control of distinct cis-regulatory elements, including the kappa intron enhancer (iE kappa) and the kappa 3' enhancer (3'E kappa). The active enhancers and expression of immunoglobulin is generally considered to be restricted to B lymphocytes. However, accumulating evidence indicated that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cell lines, express immunoglobulins. The mechanisms underlying the expression of Igs in nonlymphoid cells remain unknown. On the basis of our previous finding that expression of kappa light chain in NPC cells can be upregulated by EBV-encoded latent membrane protein 1(LMP1) through the activation of NF-kappaB and AP-1 signaling pathways, we thus use NPC cells as model to further explore the molecular mechanisms of nonlymphoid cells expressing Ig kappa.ResultsIn this study, luciferase reporter plasmid containing human wild-type iE kappa, and its derivative plasmids containing mutant binding sites for transcription factor NF-kappaB or AP-1 were constructed. Luciferase reporter assays demonstrate iE kappa is active in Ig kappa-expressing NPC cells and LMP1 expression can upregulate the activity of iE kappa in NPC cells. Mutation of the NF-kappaB or AP-1 site within and downstream the iE kappa, inhibition of the NF-kappaB and AP-1 pathways by their respective chemical inhibitor Bay11-7082 and SP600125 as well as stable or transient expression of dominant-negative mutant of I kappaB alpha (DNMI kappaB alpha) or of c-Jun (TAM67) indicate that both sites are functional and LMP1-enhanced iE kappa activity is partly regulated by these two sites. Gel shift assays show that LMP1 promotes NF-kappaB subunits p52 and p65 as well as AP-1 family members c-Jun and c-Fos binding to the kappa NF-kappaB and the kappa AP-1 motifs in vitro, respectively. Both chemical inhibitors and dominant negative mutants targeting for NF-kappaB and AP-1 pathways can attenuate the LMP1-enhanced bindings. Co-IP assays using nuclear extracts from HNE2-LMP1 cells reveal that p52 and p65, c-Jun and c-Fos proteins interact with each other at endogenous levels. ChIP assays further demonstrate p52 and p65 binding to the kappaB motif as well as c-Jun and c-Fos binding to the AP-1 motif of Ig kappa gene in vivo.ConclusionThese results suggest that human iE kappa is active in Ig kappa-expressing NPC cells and LMP1-stimulated NF-kappaB and AP-1 activation results in an augmenting activation of the iE kappa. LMP1 promotes the interactions of heterodimeric NF-kappaB (p52/p65) and heterodimeric AP-1 (c-Jun/c-Fos) transcription factors with the human iE kappa enhancer region are important for the upregulation of kappa light chain in LMP1-positive nasopharyngeal carcinoma cells.

Dataset Information

ATP1B3 Protein Modulates the Restriction of HIV-1 Production and Nuclear Factor ? Light Chain Enhancer of Activated B Cells (NF-?B) Activation by BST-2.

Publications

ATP1B3 Protein Modulates the Restriction of HIV-1 Production and Nuclear Factor κ Light Chain Enhancer of Activated B Cells (NF-κB) Activation by BST-2.

Similar Datasets

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