On June 14th, Cell Reports, a sub-journal of the international academic journal Cell, published online a research paper completed by researchers from the Institute of Biochemistry and Cell Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Institute of Pasteur, and University of Pennsylvania School of Medicine, USA Structural and Biological Features of FOXP3 Dimerization Relevant to Regulatory T Cell Function. The study found that lysine acetylation regulated the assembly of the FOXP3 protein complex, and resolved the structure of the dimer of the leucine domain, revealed the molecular basis of the FOXP3 protein-related physiological functions, and provided a deeper understanding of FOXP3 in normal and pathological environments. The assembly of the complex has important guiding significance.
FOXP3 is a key transcriptional regulatory protein that determines the differentiation and function of regulatory T cells (Treg), and is mainly expressed in natural regulatory T cells (nTreg) and inducible regulatory T cells (iTreg). FOXP3 gene transcription and protein expression are necessary steps in the development and differentiation of functional FOXP3 + Treg. Further understanding of the positive and negative regulation of FOXP3 protein assembly under inflammatory conditions will treat immune-related diseases such as infectious diseases and autoimmune diseases , Tumors, organ transplants, etc. to provide new drug targets and clinical interventions.
In the past few years, the team found that the physiological function of FOXP3 + Treg cells depends on the post-translational modification of FOXP3 protein and the assembly of transcription macromolecular complexes (Li et al Immunol Rev 2006; Li et al PNAS 2007; Li et al Curr Opin Immunol. 2007; Li et al Int Immunol. 2007; Li et al Cell Cycle 2007; Samanta and Li et al PNAS 2008; Li et al Immunology 2008; Zhou et al Immunol Res. 2008; Zhou et al Int Immunopharmacol. 2009; Xiao et al Curr Opin Immunol. 2010; Chen et al Int Immunopharmacol. 2011; Gao et al Genes Immun. 2012), this systematic work has recently been repeatedly confirmed by other different research groups (Bettini et al Immunity 2012; Darce et al Immunity 2012) , Gradually known in the art and widely cited.
On this basis, Song Xiaomin of the Institute of Biochemistry and Cell Biochemical Analysis found that FOXP3 protein can form a homodimer through its leucine domain, and then form a multimer with dimer as the basic unit. Shanghai University of Pasteur Li Bin research group doctoral students Yiyi Yi and Li Zhiyuan found that the combined treatment of the deacetylase inhibitor TSA and Nico resulted in the depolymerization of the high molecular weight FOXP3 macromolecular complex. According to the analysis of protein crystal structure, Zhou Zhaocai's research group of Biochemical and Cell Research found that the mutations of K250 and K252 in human X-linked autoimmune disease (IPEX) will directly affect the oligomerization of FOXP3 protein. Xiao Yan and Wang Qiang from the Mark I Greene laboratory of the University of Pennsylvania School of Medicine found that FOXP3 multimer formation is essential for Treg function through structure-based point mutation analysis, and found that TGF-b stimulation can cause FOXP3 protein non-K250 and non-K252 Site acetylation.
This study reveals for the first time that the assembly of FOXP3 transcriptional complex is regulated by post-translational modification of proteins, such as acetylation modification, which is of great significance for further understanding of abnormal assembly of FOXP3 complex under pathological conditions.
The research was supported by the first National Natural Science Foundation of China and the National Institutes of Health Biomedical Cooperation Pilot Project and National 973 Project.
Acetylation regulates the assembly of the FOXP3 complex: the total molecular weight of the FOXP3 protein complex in HA-FOXP3 + Jurkat T cell nuclear extracts treated with the deacetylation inhibitor Nico and TSA decreases.
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