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HDAC6 deacetylates TRIM56 to negatively regulate cGAS-mediated type I interferon response

ABSTRACT: Histone deacetylase 6 (HDAC6), a member of the class IIB HDAC family, has distinct biological functions through primarily deacetylating cytoplasmic non-histone proteins. However, its regulatory role in response to DNA virus infection remains elusive. Herein, we find that HDAC6 is a negative regulator of the cGAS-STING signaling pathway. HDAC6 deacetylase activity is increased in the early stage of Herpes simplex virus 1 (HSV-1) infection, and HDAC6 deficiency or inhibition of its deacetylase activity markedly promotes the activation of the cGAS-STING axis, resulting in increased expression of type I interferon (IFN) and a decrease in HSV-1 infection. Consistently, the Hdac6-/- mice exhibit increased resistance to HSV-1 infection and HSV-1 induced encephalitis (HSE). The HDAC6-interactome and Acetylome proteomics assays reveal that HDAC6 interacts with and deacetylates Tripartite motif protein 56 (TRIM56) at K110 within the B-box1 domain, leading to the reduced monoubiquitination and DNA binding of cGAS by TRIM56. In addition, acetylation of TRIM56 K110 is key to its binding to HDAC6 and regulating the IFN response, as evidenced by the opposing outcomes observed upon overexpressing TRIM56 K110Q and K110R on the cGAS-STING axis. Overexpression of TRIM56 K110Q further enhances protection against HSV-1 infection and HSE pathogenesis in mice, alongside increased activation of the cGAS-STING-IFN axis. Interestingly, TRIM56 displays species-specific K110, which differentially regulates the IFN response in humans and mice. Furthermore, HDAC6 accumulates in the cytoplasm and is phosphorylated by the viral protein US3, which increases its deacetylase activity and interaction with TRIM56 in the early infection stage. Together, our findings disclose that HDAC6 negatively regulates cGAS activation through TRIM56 deacetylation, suggesting a potential antiviral strategy by inhibiting HDAC6 activity.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Chen chenzixin

LAB HEAD: Zixin Chen

PROVIDER: PXD046808 | Pride | 2024-12-21

REPOSITORIES: Pride

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Project description:Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive T cell immunity.

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HDAC6 deacetylates TRIM56 to negatively regulate cGAS-mediated type I interferon response

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