PXD046808

PXD046808 is an original dataset announced via ProteomeXchange.

Title	HDAC6 deacetylates TRIM56 to negatively regulate cGAS-mediated type I interferon response
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-12-21
AnnouncementXML	Submission_2024-12-21_07:37:56.269.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chen chenzixin
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-09 01:33:28	ID requested
⏵ 1	2024-12-21 07:37:56	announced

10.1038/S44319-024-00358-5;

submitter keyword: HSV-1, TRIM56, cGAS, HDAC6, IFN-I, Deacetylation

Zixin Chen
contact affiliation	Guangdong Cardiovascular Institute, Medical Research Institute, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University
contact email	chenzixin@gdph.org.cn
lab head
Chen chenzixin
contact affiliation	Guangdong Cardiovascular Institute, Medical Research Institute, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University
contact email	chenzixin@gdph.org.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046808
     1. Label: PRIDE project
     2. Name: HDAC6 deacetylates TRIM56 to negatively regulate cGAS-mediated type I interferon response