肖能明 Xiao Nengming, Ph.D.
教授，课题组组长
电话: +86-592-2880352
Email:nengming@xmu.edu.cn
2000年7月毕业于北京师范大学生命科学学院，获理学学士学位；
2006年1月毕业于北京大学生命科学学院，获理学博士学位；
2006年8月至2009年4月在美国斯克利普斯研究所从事博士后研究；
2009年5月至2010年5月在美国克利夫兰医学中心从事博士后研究；
2010年6月至2014年9月在美国拉霍亚过敏与免疫研究所从事博士后研究；
2014年12月至今，厦门大学生命科学学院教授。
July2000, B.S. Beijing Normal University;
January2006, Ph.D., Peking University;
August 2006-April 2009, Postdoctoral Fellow, The Scripps Research Institute, La Jolla, California, USA;
May 2009-May 2010, Postdoctoral Fellow, Cleveland Clinic, Cleveland, Ohio, USA;
June 2010-September 2014, Postdoctoral Fellow, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
December 2014-present, Professor, School of Life Sciences, Xiamen University, Xiamen, China.
研究领域（Research Area)
免疫系统是人和动物体内帮助抵御入侵病原体和清除体内肿瘤细胞的防御系统。高等动物的免疫系统分为天然免疫系统和适应性免疫系统。顾名思义，天然免疫是与生俱来的，在进化上是保守的，起源于低等生物。天然免疫为机体抵御病原体入侵提供第一道防线，可迅速对大部分的病原体进行抵抗，但是不能提供长久的免疫反应，也不能特异性地针对特定的病原体。适应性免疫系统是脊椎动物所特有的，在出生后完成发育；并且只在宿主受到抗原刺激时才起作用。
The immune system is the defense system that protects host from invading pathogens and clears tumors cells. The vertebrate immune system is comprised of innate and adaptive immune system. As the name implies, the innate immune system is installed along with birth, and is evolutionarily conserved and primitive. The innate immune system provides the first line of defense against invading pathogens. It is always immediately available to combat a wide range of pathogens but does not lead to lasting immunity and is not specific for any individual pathogen. Adaptive immune system is unique to vertebrates,is established after birth, and does not come into play until there is antigenic challenge to the organism.
根据参与免疫应答的细胞类型及其效应机制的不同，适应性免疫可分为T细胞介导的细胞免疫应答和B细胞介导的体液免疫应答。生发中心（Germinal Center, GC）反应是体液免疫应答中最重要的生理过程。只有通过生发中心选择，被特异性抗原活化的B细胞才可能发育分化成为长效记忆性B细胞以及分泌长效、高亲和力抗体的浆细胞。这一生发中心选择过程是受到滤泡辅助性T细胞（Follicular helper T cells, TFH）的控制。因此，TFH帮助B细胞分化的分子机制是所有疫苗研制的理论基础。
Based on the cell types involved, adaptive immunity can be classified into T cell-mediated cellular immunity and B cell-mediated humoral immunity. The germinal center reaction is the most important physiological process in humoral immunity. Only through germinal center selection, antigen-activated B cells can differentiate into long-lived memory B cells and plasma cells secreting high affinity antibodies. This process is controlled by Follicular helper T cells (TFH). Therefore, elucidating the cellular and molecular mechanisms underlying T cell help to B cell is of critical importance for the design of better vaccines.
Bcl-6是指导TFH分化的关键转录因子，而可诱导性共刺激因子受体ICOS对TFH分化也至关重要，它能够通过PI3K-Akt信号通路诱导Bcl-6的表达。我们的研究发现转录因子Foxo1可能通过抑制Bcl-6的表达来阻断TFH分化，进一步研究表明，ICOS-PI3K-Akt信号通路对Foxo1进行磷酸化后，需要泛素连接酶Itch对Foxo1进行泛素化修饰，并导致其降解，从而促进TFH的分化。我们的研究结果揭示了泛素连接酶Itch和转录因子Foxo1在TFH分化中的重要作用。我们将继续围绕Bcl-6如何被细胞-细胞接触信号、细胞代谢等信号通路诱导表达来研究TFH分化的调控机制。我们主要利用各类基因改造小鼠，构建一些小鼠免疫疾病模型(细菌、病毒感染等)，来研究目的基因在免疫系统，特别是在TFH分化中的的功能，并通过细胞模型来研究其分子作用机制和信号通路。
Bcl-6 is an essential transcription factor that instructs the program of TFH differentiation.Inducible Costimulator (ICOS)also plays a critical role in this process, by inducing the expression of Bcl-6 through PI3K-Akt signaling pathway. Our study demonstrated that transcription factor Foxo1 inhibits TFH differentiation,bysuppressing Bcl-6 expression. ICOS-PI3K-Akt signaling leads to the phosphorylation of Foxo1, which is subsequently targeted for ubiquitination and degradation by E3 ubiquitin ligase Itch. Itch-deficient CD4+ T cells fail to degrade Foxo1 upon ICOS-PI3K-Akt signaling, and therefore, exhibit impaired Bcl-6 induction and TFH differentiation. Hence, our study revealed the important roles of Itch and Foxo1 in TFH differentiation. In the future, we will focus on the molecular mechanisms underlying Bcl-6 induction and regulation by upstream signaling pathways, including cell-cell contact and cell metabolism. We will investigate functions of candidate genesin the immune system, especially in TFH differentiation, by utilizinggenetically modified mice and immune disease models (such as bacterial and viral infections). For genes with important functions, we will elucidate their cellular and molecular mechanisms of action by employing multiple experimental approaches.
代表性论文 (Selected Publications, *Co-first author, #corresponding author)
1. Chen R, Bélanger S, Frederick MA, Li B, Johnston RJ, Xiao N, Liu YC, Sharma S, Peters B, Rao A, Crotty S#, Pipkin ME#. In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation.Immunity. 2014 Aug 21;41(2):325-38.
2. Sabouri AH, Marcondes MC, Flynn C, Berger M, Xiao N, Fox HS, Sarvetnick NE#. TLR signaling controls lethal encephalitis in WNV-infected brain.Brain Res. 2014 Jul 29;1574:84-95.
3. Xiao N, Eto D, Elly C, Peng G, Crotty S#,Liu YC#. The E3 ubiquitin ligase Itch is required for the differentiation of T follicular helper cells. Nat Immunol. 2014 Jul;15(7):657-66.
4. Yu M, Zhou H, Zhao J, Xiao N, Roychowdhury S, Schmitt D, Hu B, Harding CV, Hise AG, Hazen SL, Defranco AL, Fox PL, Morton RE, Dicorleto PE, Febbraio M, Nagy LE, Smith JD, Wang JA, Li X#. MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. J Exp Med. 2014 May 5; 211(5):887-907.
5. Burkart C, Arimoto KI, Tang T, Cong X, Xiao N, Liu YC, Kotenko SV, Ellies LG, Zhang DE#. Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10. EMBO Mol Med. 2013 Jul;5(7):967-82.
6. Arnold CN, Barnes MJ, Berger M, Blasius AL, Brandl K, Croker B, Crozat K, Du X, Eidenschenk C, Georgel P, Hoebe K, Huang H, Jiang Z, Krebs P, La Vine D, Li X, Lyon S, Moresco EM, Murray AR, Popkin DL, Rutschmann S, Siggs OM, Smart NG, Sun L, Tabeta K, Tomisato W, Webster V, Won S, Xia Y, Xiao N, Beutler B#. ENU-induced phenovariance in mice: inferences from 587 mutations. BMC Res Notes. 2012 Oct 24;5(1):577.
7. Cui W, Xiao N, Xiao H, Zhou H, Yu M, Gu J, Li X#. β-TrCP-Mediated IRAK1 Degradation Releases TAK1-TRAF6 from the Membrane to the Cytosol for TAK1-Dependent NF-κB Activation.Mol Cell Biol. 2012 Oct;32(19):3990-4000.
8. Siggs OM*, Xiao N*, Wang Y, Shi H, Tomisato W, Li X, Xia Y, Beutler B#. iRhom2 is required for the secretion of mouse TNFα. Blood. 2012 Jun 14;119(24):5769-71.
9. Xiao N, Eidenschenk C, Krebs P, Brandl K, Blasius AL, Xia Y, Khovananth K, Smart NG, Beutler B#. The Tpl2 mutation sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease.J Immunol. 2009 Dec 15;183(12):7975-83.
10. Jimenez-Dalmaroni MJ, Xiao N, Corper AL, Verdino P, Ainge GD, Larsen DS, Painter GF, Rudd PM, Dwek RA, Hoebe K#, Beutler B#, Wilson IA#. Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2.PLoS One. 2009 Oct 22;4(10):e7411.
11. Brandl K, Rutschmann S, Li X, Du X, Xiao N, Schnabl B, Brenner DA, Beutler B#.Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response.ProcNatlAcadSci U S A. 2009 Mar 3;106(9):3300-5.
12. Xu L*, Xiao N*, Liu F, Ren H, Gu J#. Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria.ProcNatlAcadSci U S A. 2009 Feb 3;106(5):1530-5.