HDAC5 enhances IRF3 activation and is targeted for degradation by protein C6 from orthopoxviruses including Monkeypox virus and Variola virus

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113788 - 113788

Published: March 1, 2024

Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection a restriction factor for VACV herpes simplex type 1. Here, report promotes interferon regulatory 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss HDAC5-mediated IRF3 restored by re-introduction but not HDAC1 HDAC4. The antiviral activity antagonized protein C6 orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, variola. Infection many these viruses induces proteasomal degradation HDAC5, alone can induce degradation. Mechanistically, binds to dimerization domain prevents homodimerization heterodimerization with Overall, this study describes as positive regulator provides mechanistic insight into how poxviral antagonize its function.

Language: Английский

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HIV-1 Vpr alters cellular transcription by targeting the PAF1 complex

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

ABSTRACT Innate immunity represents the first line of defence against viral infections, and successful pathogens like HIV-1 have evolved mechanisms to bypass these barriers. The PAF1 complex (PAF1c) has emerged as a key regulator antiviral innate immune responses, inhibiting replication various viruses, including HIV-1. While its role in transcription regulation is well documented, little known about how PAF1c inhibits circumvents this activity. Here we demonstrate that Vpr induces rapid transient downmodulation shortly after infection, process correlates with significant transcriptomic changes within host cell. Transcriptomic profiling reveals knockdown mirrors many gene expression induced by indicating antagonism means which may modulate favour replication. Further, show loss leads suppression interferon-stimulated genes (ISGs) several restriction factors. Overall, evidence supports emerging broad transcriptional program, but also suggests specific anti-HIV activity countered Vpr.

Language: Английский

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HIV capsids: orchestrators of innate immune evasion, pathogenesis and pandemicity

Journal of General Virology, Journal Year: 2025, Volume and Issue: 106(1)

Published: Jan. 13, 2025

Human immunodeficiency virus (HIV) is an exemplar virus, still the most studied and best understood a model for mechanisms of viral replication, immune evasion pathogenesis. In this review, we consider earliest stages HIV infection from transport virion contents through cytoplasm to integration genome into host chromatin. We present holistic virus-host interaction during pivotal stage infection. Central process capsid. The last 10 years have seen transformation in way understand capsid structure function. review key discoveries our latest thoughts on as dynamic regulator innate chromatin targeting. also accessory proteins Vpr Vpx because they are incorporated particles where collaborate with capsids manipulate defensive cellular responses argue that effective regulation uncoating immunity define pandemic potential pathogenesis, how comparison different lineages can reveal what makes lentiviruses special.

Language: Английский

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HIV-1 Vpr drives epigenetic remodeling to enhance virus transcription and latency reactivation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Despite decades of research, the primary proviral function HIV-1 Vpr accessory protein remains enigmatic. is essential for pathogenesis in vivo and virus replication myeloid cells, but underlying cause-and-effect mechanism(s) driving these phenomena are poorly understood. Canonically, hijacks a cellular ubiquitin ligase complex to target several dozen host proteins proteasomal degradation. Many substrates were recently revealed be involved DNA damage repair (DDR), which rationalizes longstanding observation that induces constitutive activation DDR signaling. Here, we use combination functional, biochemical, genetic approaches establish clear mechanistic link between Vpr-induced signaling remodeling epigenetic landscape enhance promoter activity during acute infection reactivation from latency. Functional, genetic, bimolecular fluorescence complementation experiments reveal utilizes degradation-dependent -independent mechanisms induce segregates into two discrete pools with dedicated activities—A multimeric pool nucleus associated chromatin monomeric DCAF1 cytoplasm. nuclear environment present common subtypes worldwide provides rationale its essentiality replication. Author summary While plays an role replication, molecular remain Vpr’s best characterized ability depletion by hijacking E3-ubiquitin complex. promotes global We demonstrate linked signaling, it occurs through both mechanisms. Moreover, this circulating globally. This study novel insights how exploits pathways sheds light on function.

Language: Английский

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HIV-1 accessory protein Vpr possesses a cryptic p300-dependent transcription-promoting activity that is blocked by histone deacetylases in CD4⁺T cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Antiretroviral therapy (ART) has dramatically improved the clinical prognosis for people with HIV and prevents transmission. However, ART does not cure infection because of a persistent, latent reservoir in long-lived cells such as central memory CD4 + T (T CM ) cells. Eliminating or preventing formation will require better understanding HIV-1 latency establishment. We others have recently shown that host cell factors histone deacetylases (HDACs) are critical cellular allow entry into latency. Whether HDACs interact specific viral to regulate establishment, however, is unknown. To examine role individual accessory proteins, we constructed panel reporter strains, each expressing single protein, examined them primary T-cell model. Interestingly, found HDAC inhibitor (HDACi) vorinostat potently enhances effect protein Vpr promoting expression infected cells, suggesting possesses cryptic transcription-promoting activity restricted by HDACs. This was dependent on p300-binding domain inhibited selective p300 acetyltransferase inhibitor. also resulted significant increase proportion phenotype. Furthermore, observed were more resistant Vpr-induced apoptosis/cell death than other subtypes, indicating during selects proviruses Overall, these findings suggest plays an important shaping results, part, from HDAC-mediated restriction Vpr’s activity. Understanding how shape establishment aid development new latency-targeting therapies. Author Summary Although antiretroviral effective at treating HIV, remains elusive. The obstacle presence latently which virus persists despite therapy. Recent work sizable fraction this forms near time initiated, it may be possible prevent some forming. prevention enters latency, including gene silenced. therefore sought interaction between proteins turning off that, whereas turns expression, block Second, leads relative type harbors virus. Our silencing persistence certain types developing approaches targeting

Language: Английский

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