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    The Crosstalk of mTOR-regulated metabolic program with epigenetics and necroptosis in homeostasis and inflammation

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    Seminar Institut Cochin

    Monday 30th September 2019 - 12:00 - Room conference Rosalind Franklin, 2nd floor

     


    Hui Xiao

    Institut Pasteur of Shanghai, Chinese Academy of Sciences, China

     

     invited by Serge Benichou

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Abstract

    The research goal of my lab is to decipher the signaling mechanisms by which the innate receptors TLRs, CLRs and RLRs regulate both innate and adaptive immune responses, and develop novel approaches to control infection, autoimmune disease and cancer. Recently, we found that mTOR-regulated metabolic programming is intrinsically integrated into the TLR signaling in the regulation of immunity and inflammation. On one hand, we found that the mTOR-regulated metabolic program, featured with fatty acid synthesis, has a profound impact on DC’s ability to trigger CD8 T cell response. Perturbing mTOR activation in DCs led to compromised acetyl-CoA synthesis, impaired histone acetylation on the promoters of a subset of genes such as Il7 and H2b1, thereby affecting CD8 T cell survival and anti-tumor immunity. On the other hand, we found that the TSC1-mTOR pathway also represents a metabolic and innate immune checkpoint for necroptosis and inflammation in the gut. mTOR hyperactivation triggered by western-diet or Tsc1-ablation led to epithelium necroptosis, barrier disruption, and predisposition to colitis and cancer. Mechanistically, we uncovered a critical role for TSC1-mTOR in restraining the expression and activation of RIPK3 in gut epithelium through autophagy-dependent degradation, therefore revealing a previously unsuspected link between Western-diet/microbiota and necroptosis in the pathogenesis of IBD and colon cancer. Together, our results support the emerging notion that the innate receptor signaling can integrate the metabolic program in the regulation of immunity and inflammation. 

     

    Some publications

    1. Shi L, Chen X, Zang A, Li T, Hu Y, Ma S, Lü M, Yin H, Wang H, Zhang X, Zhang B, Leng Q*, Yang J*, Xiao H*. TSC1/mTOR-controlled metabolic-epigenetic cross talk underpins DC control of CD8 T-cell homeostasis. PLoS Biol. 2019 17(8): e3000420.
    2. Wang W, Deng Z, Wu H, Zhao Q, Li T, Zhu W, Wang X, Tang L, Wang C, Cui SZ, Xiao H*, Chen J*. A small secreted protein triggers a TLR2/4-dependent inflammatory response during invasive Candida albicans infection. Nat Commun. 2019, 10(1):1015.
    3. Ma S, Wan X, Deng Z, Shi L, Hao C, Zhou Z, Zhou C, Fang Y, Liu J, Yang J, Chen X, Li T, Zang A, Yin S, Li B, Plumas J, Chaperot L, Zhang X, Xu G, Jiang L, Shen N, Xiong S, Gao X, Zhang Y, Xiao H*. (2017) Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs. J Exp Med, 2017, 214:1471-1491.
    4. Deng Z, Ma S, Zhou H, Zang A, Fang Y, Li T, Shi H, Liu M, Du M, Taylor PR, Zhu HH, Chen J, Meng G, Li F, Chen C, Zhang Y, Jia XM, Lin X, Zhang X, Pearlman E, Li X, Feng GS, Xiao H*. (2015) Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal Th17 responses. Nat Immunol, 2015, 16:642-652.
    5. Du M, Liu J, Chen X, Xie Y, Yuan C, Xiang Y, Sun B, Lan K, Chen M, James SJ, Zhang Y, Zhong J, Xiao H*. Casein Kinase II Controls TBK1/IRF3 Activation in IFN Response against Viral Infection. J Immunol, 2015, 194:4477-88.
    6. Xiao H#, Gulen MF, Qin J, Yao J, Bulek K, Kish D, Altuntas CZ, Walde D, Ma C, Zhou H, Tuohy VK, Fairchild R, de la Motte C, Cua D, Vallance BA, and Li X. The Toll-Interleukin-1 receptor member SIGIRR regulates colonic epithelia homeostasis, inflammation and tumorigenesis. Immunity, 2007, 26:461-75.

     

     

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