杰青siRNA技术受体研究成果登《Cell》子刊

　　

生物通报道，中国科学院上海生命科学研究院健康所05国家杰出青年科学基金得主戈宝学博士在RIG-I抗感染调控研究方面取得新的进展，文章发表在An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis上。

 

该研究工作得到了国家自然科学基金、科技部973和卫生部重大专项的支持。

 

RIG-I是近年来发现的一种能够识别病毒RNA的细胞质内受体，能够识别多种RNA 病毒如丙型肝炎病毒（hepatitis C virus (HCV)）病毒的双链RNA组分，并通过自身的CARD与下游信号分子MAVS的CARD相互作用来传递信号，激活细胞转录因子IRF-3和NF-κB，使其进入细胞核内，诱导抗病毒干扰素的表达，从而启动固有免疫应答和调节随后的获得性免疫应答，增强机体抵抗病毒感染的能力。

 

特异性的siRNA“knock-down”RIG-I 或基因敲除RIG-I降低了巨噬细胞对细菌的吞噬能力。此外，RIG-I基因剔除小鼠对细菌感染较正常小鼠的敏感性明显增强。这一研究结果表明RIG-I是寄主抵抗细菌感染的一个非常重要的调控分子。

生物通推荐原文检索

An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis

Ling Kong1,4,6,Lei Sun1,4,6,Hongxin Zhang2,Qin Liu1,Ye Liu1,Linhua Qin1,Guojun Shi1,4,Jun-Hao Hu1,4,Ajing Xu1,Yue-Ping Sun2,Dangsheng Li5,Yu-Fang Shi1,Jing-Wu Zang1,Jiang Zhu3,Zhu Chen3,Zhu-Gang Wang2,3,,andBao-Xue Ge1,,

 

1 The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai 200025, China

2 Laboratory of Genetic Engineering, Department of Medical Genetics, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China

3 State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, RuiJin Hospital, Shanghai 200025, China

4 Graduate School of Chinese Academy of Sciences, Beijing 100039, China

5 Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

 

 

Corresponding author

 

Corresponding author

 

6 These authors contributed equally to this work

 

 

 

Summary

Retinoic acid-inducible gene-I (RIG-I) plays an important role in antiviral response by recognizing double-stranded RNA. Here we demonstrate an unanticipated role of RIG-I in Toll-like receptor (TLR)-stimulated phagocytosis. Stimulation with lipopolysaccharide (LPS), a ligand of TLR4, induced the expression of RIG-I in macrophages. Depletion of RIG-I by RNAi or gene targeting inhibited the LPS-induced phagocytosis of bacteria. Cellular processes involved in phagocytosis, such as small GTPase Cdc42/Rac1 activation, actin polymerization, and actin-regulator Arp2/3 recruitment, were also impaired in RIG-I-deficient macrophages activated by LPS. Moreover, RIG-I/ mice were found to be more susceptible to infection with Escherichia coli as compared to wild-type mice. Thus, the regulatory functions of RIG-I are strikingly broad, including a role not only in antiviral responses but in antibacterial responses as well.

 

戈宝学

博士，研究员，博士生导师，教授

信号转导研究组组长

 

研究方向

从事免疫系统中的细胞信号转导机制研究，特别是细胞内MAP激酶(MAPK)和MAPK去磷酸化酶(MKP)及TLR(Toll-like Receptor)信号转导通路的调控机制研究。此外，也研究自然杀伤细胞(NK)细胞中细胞杀伤活性的信号转导调节机制及抗炎中药组分调节细胞因子产生的机制。

 

主要成果

1. 发现p38 MAP激酶与支架蛋白TAB1的相互作用可以激活p38，而不需要MAPKK的作用。因此提出在细应急过程中p38的激活除了经典 MAPKKK-MAPKK-MAPK cascade外还有其他的通路(Science, 2002, 附评论)。同期还发现了TAB1的选择性剪切产物TAB1b能与p38a相互作用，而不与TAK相互作用(JBC, 2003)。

2. 发现NK细胞抑制性受体KIR2DL1，KIR2DL2，KIR2DL3可以和多功能分子beta-arrestin2特异性的结合，并影响KIR2DL1下游信号转导分子Vav和ERK的激活及NK细胞的杀伤活性(Nature Immunology, 2008, 附评论)。

3. 发现small GTPases在toll样受体介导的吞噬作用中起着关键作用，同时，我们发现细胞骨架蛋白Actin可以调节small GTPases的激活，并影响巨噬细胞的吞噬能力(Cell Research, 2008, 封面, 附评论)。另外，研究发现RIG-I(Retinoic acid-inducible gene-I)，一种存在于胞浆内的病毒双链RNA识别蛋白，影响巨噬细胞的吞噬能力。深入研究发现，在巨噬细胞和293细胞中，RIG-I和细胞骨架蛋白actin有相互作用而且共定位(Cell Host & Microbe, 2009)。

 

学习经历

1987             中国北京农业大学昆虫学学士

1999             美国加州大学遗传学博士

1999-2002        美国Scripps研究所免疫学部博士后

 

工作简历

1993-1999        美国加利福尼亚大学里弗赛德(河边)分校助研

1999-2002        美国Scripps研究所博士后，高级助研

2002-至今        中科院上海生命研究院/上海交通大学医学院健康科学研究所课题组长，研究员，博士生导师

 

荣誊(证书,称号,会员)

2001        美国国立卫生院博士后奖学金

2002        中国科学院“****”称号(免疫学)

2005        国家自然科学基金委“杰出青年”(免疫学)

2006        上海市第一届科技创新人才奖

2006        中国科学院“****“终期评估优秀

2008         明治乳业生命科学奖“杰出奖”

2008        谈家桢生命科学创新奖

 

近期主要论文

Kong L, Sun L, Zhang H, Liu Q, Liu Y, Qin L, Shi G, Hu JH, Xu A, Sun YP, Li D, Shi YF, Zang JW, Zhu J, Chen Z, Wang ZG, Ge BX*. (2009) An essential role for RIG-I in Toll-like receptor-mediated phagocytosis. Cell Host & Microbe, 6(2):150-61.

Cui G, Qin X, Zhang Y, Gong Z, Ge BX, Zang YQ. 2009 Berberine differentially modulates the activities of ERK, p38 MAPK and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. J Biol Chem. Aug 6. [Epub ahead of print]

Zhi Huang, Da-Peng Yan and Bao-Xue Ge*. (2008) JNK regulates cell migration through promotion of tyrosine phosphorylation of paxillin. Cell Signal. 20(11):2002-12.

Ming-Can Yu, Liu-Li Su, Lin Zou，Ling Kong, Zi-Heng Zhuang, Jun-Hao Hu, Lei Sun, Jing-Wu Zang, Jack L.Strominger, Gang Pei and Bao-Xue Ge*. (2008) An essential role for β-arrestin 2 in the inhibitory signaling of Natural Killer cells. Nature Immunology, 9(8):898-907.

Zhang NN, Shen SH, Jiang LJ, Zhang W, Zhang HX, Sun YP, Li XY, Huang QH, Ge BX, Chen SJ, Wang ZG, Chen Z, Zhu J. (2008) RIG-I plays a critical role in negatively regulating granulocytic proliferation. Proc Natl Acad Sci U S A. 105(30):10553-8.

Kong L, Ge BX*. (2008) MyD88-independent activation of a novel actin-Cdc42/Rac pathway is required for Toll-like receptor-stimulated phagocytosis. Cell Res. 18(7):745-55. (Cover Story)

Liu J, Wang ZT, Ge BX*. (2008) Andrograpanin, isolated from Andrographis paniculata, exhibits anti-inflammatory property in lipopolysaccharide-induced macrophage cells through down-regulating the p38 MAPKs signaling pathways. Int Immunopharmacol. 8(7):951-958.

Sun L, Yu MC, Kong L, Zhuang ZH, Hu JH, Ge BX*. (2008) Molecular identification and functional characterization of a Drosophila dual-specificity phosphatase DMKP-4 which is involved in PGN-induced activation of the JNK pathway. Cell Signal. 20(7):1329-1337.

Li C, Ge B, Nicotra M, Stern JN, Kopcow HD, Chen X, Strominger JL. (2008) JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity. Proc Natl Acad Sci U S A. 105(8):3017-22.