Type I interferons (IFNs) were discovered as critical antiviral cytokines, which has now been recognized to play multifaceted roles in diseases. Precise regulation of IFN-I production is critical to maintain host homeostasis in response to infections or autoimmune diseases.
A research group led by Prof. WANG Hongyan from Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences(CAS), recently discovered novel function of TET3 in macrophages against viral infection.
In this study, researchers screened the expression levels of the TET family members in primary macrophage. After activating the toll-like receptor 3 (TLR3) pathway, retinoic acid-inducible gene I (RIG-I) pathway or melanoma differentiation-associated gene 5 (MDA-5) pathway, the mRNA levels of TET3 were significantly down-regulated. TET3 deficiency increased the production of type I IFN, including IFN-β and IFN-α, as well as anti-viral effectors including 2'-5'-oligoadenylate synthase 1A (OAS1a), which resulted in the elevated viral clearance in macrophages.
Further study revealed that enzymatic activity of TET3 was dispensable for the suppression of IFN-β production. Instead, the catalytic domain of TET3 interacted with histone deacetylase 1 (HDAC1) and SIN3A. This interaction enhanced their binding to the Ifnb1 promoter and repressing Ifnb1 transcription.
This study provides a novel understanding of TET3 function. Instead of acting as a DNA demethylase, TET3 functions as a scaffold signaling protein in macrophages for gene regulation. Meanwhile, this work might help to develop new strategies to prevent type I IFN-related disease.
The study entitled “TET3 Inhibits Type I IFN Production Independent of DNA Demethylation” has been published in Cell Reports on July 14th, 2016.
This work was done in collaboration with Prof. XU Guoliang and Prof. SUN Bing from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences.
This work was financially supported by grants from the Ministry of Science and Technology of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, the National Natural Science Foundation of China, the State Key Laboratory of Cell Biology, SIBCB, SIBS, CAS and the Program of the Chinese Academy of Sciences.
AUTHOR CONTACT:
WANG Hongyan, Ph.D., Professor
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
320 Yueyang Road, Shanghai 200031, China
Tel: 86-21-54921086
Email: hongyanwang@sibcb.ac.cn
KEYWORDS:
Macrophage, TET3, HDAC1, SIN3A, anti-viral response
NEWS ABSTRACT:
Type I interferon is the critical cytokine maintaining host homeostasis and is under precise regulation. This study demonstrates that TET3 negatively regulates the production of type I interferon and anti-viral effectors through recruiting the transcription repressors, HDAC1 and SIN3A, to the Ifnb1 promoter. This work provides the first evidence to elucidate that TET3 functions as a signaling scaffold protein for gene regulation independent of its DNA demethylase activity.
Illustration of type I IFN regulation by TET3. In wild type cell, expression of TET3 is decreased upon viral infection. TET3 recruits HDAC1 and SIN3A, which are the well-known transcription repressors, to the Ifnb1 promoter to suppress the transcription of Ifnb1. In TET3 deficient cells, HDAC1 and SIN3A are unable to bind to the Ifnb1 promoter, thus enhancing the production of IFN-β. (Image provided by Prof. WANG Hongyan’s lab)
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