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Hepatitis C Virus Infection Activates a Novel Innate Pathway Involving IKKα in Lipogenesis and Viral Assembly

ABSTRACT: Hepatitis C virus interacts extensively with host factors not only to establish productive infection but also to trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IKKα is a critical host factor for HCV. Here we describe a novel NF-κB-independent and kinase-mediated nuclear function of IKKα in HCV assembly. HCV infection, through its 3’-untranslated region, interacts with DDX3X to activate IKKα, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving SREBPs. This novel innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKKα suppress HCV infection and IKKα-induced lipogenesis, offering a proof-of-concept approach for novel HCV therapeutic development. Our results show that HCV commands a novel mechanism to its advantage by exploiting intrinsic innate response and hijacking lipid metabolism, which likely contributes to a high chronicity rate and the pathological hallmark of steatosis in HCV infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46528 | GEO | 2013/05/08

SECONDARY ACCESSION(S): PRJNA201062

REPOSITORIES: GEO

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Hepatitis C Virus Infection Activates a Novel Innate Pathway Involving IKKα in Lipogenesis and Viral Assembly

Project description:Hepatitis C virus interacts extensively with host factors not only to establish productive infection but also to trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IKKα is a critical host factor for HCV. Here we describe a novel NF-κB-independent and kinase-mediated nuclear function of IKKα in HCV assembly. HCV infection, through its 3’-untranslated region, interacts with DDX3X to activate IKKα, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving SREBPs. This novel innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKKα suppress HCV infection and IKKα-induced lipogenesis, offering a proof-of-concept approach for novel HCV therapeutic development. Our results show that HCV commands a novel mechanism to its advantage by exploiting intrinsic innate response and hijacking lipid metabolism, which likely contributes to a high chronicity rate and the pathological hallmark of steatosis in HCV infection. Cells were treated with either non-targeting control siRNA or siRNA against IKKalpha. After 72 h, cells were either mock infected or infected with HCV JFH-1 strain with the M.O.I. of 0.5.

2013-05-08 | E-GEOD-46528 | biostudies-arrayexpress

IKKα promotes intestinal tumorigenesis

Project description:Depending on the tumor type IκB kinase α (IKKα) can act as tumor promoter or tumor suppressor in various malignancies. Here we demonstrate a key function of IKKα in the suppression of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of IFNγ expressing M1-like myeloid cells. In IKKα mutant mice M1-like polarization is not controlled in a cell autonomous manner but depends rather on the interplay of both IKKα mutant tumor epithelia and immune cells. Tamoxifen-inducible β-catc.a. mice comprise an excellent model to study Wnt-dependent tumor initiation. These mice are characterized by IEC-restricted stabilization of β-catenin causing rapid expansion of intestinal crypts and loss of differentiated IEC. To further explore the underlying IKKα controlled pro-proliferative mechanism, we performed a microarray analysis comparing RNA isolated from wildtype, IkkαAA/AA, β-catc.a. or β-catc.a./IkkαAA/AA IEC 15 days after the first tamoxifen administration. and within 4 weeks β-catc.a. mice succumb to this marked crypt hyperproliferation

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IKKα promotes intestinal tumorigenesis

2014-06-01 | GSE51631 | GEO

Expression data from Huh7.5.1 cells transfected with siNDRG1 or siNT

Project description:Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc Downstream-Reguated Gene 1 (NDRG1) limits productive HCV infection by inhibiting viral assembly. Interestingly, HCV infection down-regulates NDRG1 protein and mRNA expression. Loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by up-regulating MYC, which directly inhibits the transcription of NDRG1. Up-regulation of MYC also leads to reduced expression of NDRG1-specific kinase SGK1, resulting in markedly diminished phosphorylation of NDRG1. Knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both transcriptional and post-translational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by down-regulating NDRG1 via a MYC-dependent mechanism.

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NEMO is essential for directing IKKα and ATM to the sites of DNA damage

Project description:We previously demonstrated that IKKα binds to and phosphorylates ATM thus potentiating the non-homologous end joining DNA damage repair pathway in cancer cells. Hence, inhibiting IKKα enhances the efficacy of DNA damage-based anticancer therapy. Whether additional elements contribute to this resistance-related mechanism remains unknown. We here show that NEMO physically interacts with the ATM-IKKα complex before damage. Upon exposure to damaging agents, NEMO is dispensable for ATM activation, but it is required to drive active ATM and IKKα to the sites of damage thus enabling DNA damage resolution. Recognition of damaged DNA by this IKKα/NEMO/ATM complex is partially mediated by direct interaction of NEMO to histones but highly dependent on PARP1 activity. Finally, we detected increased ATR activity in NEMO-deficient cells, and that ATR inhibition potentiates the effect of chemotherapy upon NEMO or IKKα depletion. Bioinformatic analysis of public CRC datasets support the functional impact of the IKKα/NEMO/ATM pathway in patient prognosis, which could be therapeutically exploited.

2024-02-11 | PXD043552 | Pride

Quantitative Lipid Droplet Proteome Analysis Identifies Annexin A3 as a Cofactor for HCV Particle Production

Project description:Cytosolic lipid droplets (LDs) are vital to Hepatitis C Virus (HCV) infection as the putative sites of virion assembly. To identify novel regulators of HCV particle production, we performed quantitative LD proteome analysis. Huh7.5 cells were labeled by stable isotope labeling with heavy amino acids in cell culture (SILAC) and subsequently infected with an HCV Jc1 reporter virus. After selection for HCV-infected cells, equal amounts of HCV-infected and uninfected control cells were mixed, LDs were isolated and analyzed by LC-ESI-MS/MS.

2016-09-26 | PXD004707 | Pride

BRAF and IKKα involvement in DNA Damage Response

Project description:BRAF and IKKα are damage-responsive kinases required for 53BP1 and RIF1 co-recruitment to sites of DNA breaks and for timely resolution of DNA lesions. This provides a novel therapeutic opportunity based on combining BRAF or IKKα inhibitors with therapeutic agents that induce DNA damage

2019-11-14 | PXD008932 | Pride

Proximity labeling of host factor ANXA3 in HCV infection reveals a novel LARP1 function in viral entry

Project description:Hepatitis C virus (HCV) infection is tightly connected to the lipid metabolism with lipid droplets (LDs) serving as assembly sites for progeny virions. A previous LD proteome analysis identified annexin A3 (ANXA3) as an important HCV host factor that is enriched at LDs in infected cells and required for HCV morphogenesis. To further characterize ANXA3 function in HCV, we performed proximity labeling using ANXA3-BioID2 as bait in HCV-infected cells. Two of the top proteins identified proximal to ANXA3 during HCV infection were the La-related protein 1 (LARP1) and the ADP ribosylation factor-like protein 8B (ARL8B), both of which have been previously described to act in HCV particle production. In follow-up experiments ARL8B functioned as a pro-viral HCV host factor without localizing to LDs und thus likely independent of ANXA3. In contrast, LARP1 interacts with HCV core protein in an RNA-dependent manner and is translocated to LDs by core. Knockdown of LARP1 decreased HCV spreading without altering HCV RNA replication or viral titers. Unexpectedly, entry of HCV particles and E1/E2-pseudotyped lentiviral particles was reduced by LARP1 depletion, whereas particle production was not altered. Using a recombinant vesicular stomatitis virus (VSV)ΔG entry assay, we showed that LARP1 depletion also decreased entry of VSV with VSV, MERS, and CHIKV glycoproteins. Therefore, our data expand the role of LARP1 as an HCV host factor that is most prominently involved in the early steps of infection, likely contributing to endocytosis of viral particles through the pleiotropic effect LARP1 has on the cellular translatome.

2024-04-17 | PXD049182 | Pride

IKKα signaling in the nucleus or cytoplasm of keratinocytes leads to opposite skin phenotypes.

Project description:The skin exerts essential roles for the organism survival, such as environmental barrier and immune functions. IKKα is known as an essential protein for skin homeostasis. However, the functions performed by IKKα in the skin and the mechanisms it employs are largely unknown, leading to contradictory interpretations and results regarding the consequences of its deregulation in pathologies such as non-melanoma skin cancer (NMSC). Here, using our previously generated transgenic mouse models which express IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα distinctly regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, as well as the inflammatory response of the skin. As a result, N-IKKα mice show an atrophic epidermis with exacerbated terminal differentiation, reminiscent of alterations observed in patients with ichthyosis. Conversely, C-IKKα mice display a hyperplastic epidermis with impaired epidermal differentiation and pustular inflammation, resembling patients with pustular psoriasis. Interestingly, C-IKKα keratinocytes are almost devoid of nuclear IKKα due to endogenous IKKα downregulation. However, these changes in the skin of C-IKKα mice do not lead to the development of squamous cell carcinomas (SCCs), unlike N-IKKα mice, which develop spontaneous SCCs.

2024-11-14 | GSE239533 | GEO

IKKα Is Required to Maintain Skin Homeostasis and Prevent Skin Cancer

Project description:It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear, however, whether there are any innate surveillants that ensure keratinocytes undergoing terminal differentiation, preventing the disease. IKKα induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its nature function in skin cancer is unknown. Here we found that mice with IKKα deletion in keratinocytes or in hair follicle keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKα inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKα serves as an innate surveillant.

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