ABIN-1 negatively regulates NF-κB by inhibiting processing of the p105 precursor

Cohen, Shai; Ciechanover, Aaron; Kravtsova‐Ivantsiv, Yelena; Lapid, Dana; Lahav-Baratz, Shirly

doi:10.1016/j.bbrc.2009.08.074

Cited by 27 publications

(34 citation statements)

References 23 publications

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“…It has been reported that Naf1 expression inhibited NF-B activation and HIV-1 infection (37,46,51,53). Naf1 associates with A20, a zinc finger protein with deubiquitinase activity, and facilitates A20-mediated de-ubiquitination of NEMO/IKK␥ and subsequent NF-B inhibition in response of TNF-␣ (40,54,56).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Ren

Wang

et al. 2016

Journal of Biological Chemistry

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HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-B activation through binding to A20, and the loss of Naf1 controlled NF-B activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection.HIV-1 depends on host factors to complete its life cycle (1-8). Hundreds of human proteins involved in the interaction with HIV-1 for modulating viral replication have been identified by genome-wide RNA interference screen or affinitytagged protein purification using mass spectrometry (1,(3)(4)9). A comprehensive understanding of how host machineries are manipulated during HIV-1 infection can facilitate the identification of host targets for antiviral drugs or gene therapy.The CRM1 (chromosome region maintenance 1, 2 also known as exportin 1) nuclear export pathway is typically used to transport host protein cargoes and small RNAs, which has been found to engage HIV-1 regulatory protein Rev for directing the nuclear export of unspliced and partially spliced HIV-1 RNAs (10 -15). These incompletely spliced HIV-1 RNAs contain a Rev response element (RRE), and the coordinate assembly of multiple Rev molecules on RRE recruits human protein complex containing CRM1 and Ran-GTP (GTP-binding nuclear protein Ran). Rev contains a leucine-rich nuclear export signal (NES) domain located near the carboxyl terminus, through which Rev interacts with CRM1, and the Rev-RRE-CRM1/Ran-GTP complex is then transported to the cytoplasm (6, 11-16). Similarly, other retroviruses such as mouse mammary tumor virus and human T cell lymphotropic virus encode Rev-like regulatory proteins Rem or Rex, respectively, for hijacking the host CRM1 pathway to accomplish nuclear export of unspliced viral transcripts (17)(18)(19)(20)(21)(22).Several other cellular facto...

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Section: Discussionmentioning

confidence: 99%

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Ren

Wang

et al. 2016

Journal of Biological Chemistry

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“…ABIN-1 regulates IL-17--activated NF-kB signaling ABIN-1 is known to inhibit NF-kB in the context of TNF-a stimulation, and the above results suggested ABIN-1 suppressed NF-kB-dependent genes in the IL-17 pathway as well (19)(20)(21)(22). An early step in the canonical NF-kB signaling pathway is phosphorylation of the inhibitor IkBa, which leads to its degradation by the proteasome, releasing NF-kB for nuclear translocation.…”

Section: /2mentioning

confidence: 84%

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

et al. 2017

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IL-17 activates NF-κB and inducing expression of proinflammatory genes. IL-17 drives disease in autoimmune conditions, and anti-IL-17 antibodies have shown impressive success in the clinic. Although produced by lymphocytes, IL-17 predominantly signals in fibroblasts and epithelial cells. IL-17-driven inflammation is kept in check by negative feedback signaling molecules, including the ubiquitin editing enzyme A20, whose gene TNFΑIP3 is and similarly linked to autoimmune disease susceptibility. Accordingly, we hypothesized that ABIN-1 might play a role in negatively regulating IL-17 signaling activity. Indeed, ABIN-1 enhanced both tonic and IL-17-dependent NF-κB signaling in IL-17-responsive fibroblast cells. Interestingly, the inhibitory activities of ABIN-1 on IL-17 signaling were independent of A20. ABIN-1 is a known NF-κB target gene, and we found that IL-17-induced activation of NF-κB led to enhanced ABIN-1 mRNA expression and promoter activity. Surprisingly, however, the ABIN-1 protein was inducibly degraded following IL-17 signaling in a proteasome-dependent manner. Thus, ABIN-1, acting independently of A20, restricts both baseline and IL-17-induced inflammatory gene expression. We conclude that IL-17-induced signals lead to degradation of ABIN-1, thereby releasing a constitutive cellular brake on NF-κB activation.

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“…The HIV-1 LTR promoter often contains two adjacent NF-B binding sites that are crucial for initiating viral transcription (26). NF-B activity is required for efficient cellular and HIV-1 gene transcription, and Naf1 can inhibit NF-B activation (15,18,19,27). We hypothesized that Naf1 suppresses NF-B-dependent HIV-1 LTR-driven gene expression.…”

Section: Naf1 Suppresses Hiv-1 Long Terminal Repeat (Ltr)-driven Genementioning

confidence: 99%

“…Nef-associated factor 1 (Naf1), also known as ABIN-1 (A20-binding inhibitor of NF-B activation 1) and TNFAIP3 (tumor necrosis factor alpha [TNF-␣]-induced protein 3)-interacting protein 1 (15), was discovered by yeast two-hybrid screening and pulldown assays using HIV-1 Nef as bait (16). Naf1 has two isoforms, Naf1-␣ and Naf1-␤, and Naf1-␣ is the canonical isoform (16).…”

mentioning

confidence: 99%

“…Naf1 is expressed ubiquitously in human tissues, with high levels of expression in peripheral blood lymphocytes (16,17). Naf1 can increase cell surface CD4 expression (16), inhibit NF-B activation (15,18,19), and modulate HIV-1 infection and viral production (17,20). Naf1 also interacts with the HIV-1 matrix protein, and the overexpression of Naf1 inhibits HIV-1 infection (17).…”

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confidence: 99%

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Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 ⁺ T Cells

Wang

Kuang

et al. 2017

J Virol

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HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4+ T cells. Furthermore, Naf1 knockdown in resting CD4+ T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo. Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy. IMPORTANCE HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.

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ABIN-1 negatively regulates NF-κB by inhibiting processing of the p105 precursor

Cited by 27 publications

References 23 publications

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 ⁺ T Cells

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ABIN-1 negatively regulates NF-κB by inhibiting processing of the p105 precursor

Cited by 27 publications

References 23 publications

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 + T Cells

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Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 ⁺ T Cells