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Spencer, E., Jiang, J., and Chen, Z.J. (1999) Signal-induced ubiquitination of IkBa by the F-box protein, Slimb/b-TrCP. Genes & Dev. 13, 284-294.
Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., and Chen, Z.J. (2000) Activation of the IkB kinase complex requires a dimeric ubiquitin-conjugating enzyme complex and the formation of a unique polyubiquitin chain. Cell 103, 351-361.
Wang, C., Deng, L., Hong, M. Akkaraju, G.R., Inoue, J-i., and Chen, Z.J. (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-351.
Sun, L., Deng, L., Ea, C-K., Xia, Z-P., and Chen, Z.J. (2004) The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Molecular Cell 14, 289-301.
Kanayama, A., Seth, R.B., Ea, C-K, Hong, M., Shaito, A., Deng, L., and Chen, Z.J. (2004) TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Molecular Cell 15, 535-548.
Ea, C-K., Deng, L., Xia, Z-P., Pineda, G., and Chen, Z.J. (2006) Activation of IKK by TNFa requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Molecular Cell 22, 245-257.
Xu, M., Skaug, B., Zeng, W., and Chen, Z.J. (2009) A ubiquitin replacement strategy reveals distinct mechanisms of IKK activation by TNFa and IL-1b. Molecular Cell 36, 315-325.
Xia, Z.P., Sun, L., Chen, X., Pineda, G., Jiang, X., Adhikari, A., Zeng, W., and Chen, Z.J. (2009). Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 461, 114-119.
Skaug, B., Chen, J., Du, F., He, J, Ma, A., and Chen, Z.J. (2011) Direct, non-catalytic mechanism of IKK inhibition by A20. Molecular Cell 44, 559-571.
NF-κB与另一种转录因子IRF3协同作用，在病毒感染后诱导I型干扰素的产生。病毒感染后，病毒RNA被RIG-I家族的RNA解旋酶检测到。2005年，陈教授团队鉴定出蛋白质MAVS（又称IPS-1, VISA, 或CARDIF）作为RIG-I信号传导的关键适配器。MAVS位于线粒体外膜上，这一定位对于其功能至关重要，因为丙型肝炎病毒的NS3/4A蛋白酶能够有效地将MAVS从线粒体膜上切割，从而抑制干扰素的诱导。通过MAVS敲除小鼠进一步证实了MAVS在抵御RNA病毒中的关键作用。最近，陈教授团队发现RIG-I通路在检测共生细菌RNA和维持肠道稳态中也起着重要作用。
Seth, R.B., Sun, L., Ea, C., and Chen, Z.J. (2005) Identification and characterization of MAVS: a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell 122, 669-682.
Li, X-D., Sun, L., Seth, R.B., Pineda, G., and Chen, Z.J. (2005) The Hepatitis C Virus Protease NS3/4A Cleaves MAVS off the Mitochondria to Evade Innate Immunity. Proc. Natl. Acad. Sci. U S A102, 17717-17722.
Sun, Q., Sun, L., Liu, H-H., Chen, X., Seth, R.B., Forman, J. and Chen, Z.J. (2006) The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24, 633-642.
Bhoj, V.G., Sun, Q., Bhoj, E., Somers, C., Chen, X., Torres, J-P., Mejias, A., Gomez., A., Jafri, H., Ramilo, O., Chen, Z.J. (2008). MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. Proc. Natl. Acad. Sci. U S A 105, 14046-14051.
Li, X.D., Chiu, Y.H., Ismail, A.S., Behrendt, C.L., Wight-Carter, M., Hooper, L.V., and Chen, Z.J. (2011). Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc Natl Acad Sci U S A108, 17390-17395.
陈教授团队的近期研究集中在RIG-I通路的信号传导机制上。通过开发一种细胞自由系统，从检测病毒RNA到激活IRF3，陈教授团队发现泛素化在RIG-I的激活中也起到了关键作用。具体来说，RIG-I在与RNA结合后发生构象变化，暴露出其N端CARD结构域，这些结构域随后与未锚定的K63多泛素链结合。这种结合促进了RIG-I四聚体的形成，进而与MAVS相互作用并促进MAVS聚集。令人惊讶的是，MAVS的聚集通过类似朊蛋白的机制催化了线粒体上其他MAVS的聚合。电子显微镜解析了MAVS聚集体的结构，表明这种朊蛋白样机制是细胞信号传导中的普遍机制。这些MAVS的朊蛋白样纤维招募了多种泛素E3连接酶，包括TRAF2、TRAF5和TRAF6，从而有效激活胞质激酶IKK和TBK1，分别导致NF-κB和IRF3的激活。值得注意的是，MAVS被IKK和TBK1磷酸化，从而为IRF3提供了一个结合位点，这种信号诱导的磷酸化为IRF3激活增加了另一层精确调控。
Zeng, W., Xu, M., Liu, S., Sun, L., Chen, Z.J. (2009) Key role of Ubc5 and K63 polyubiquitination in viral activation of IRF3. Molecular Cell 36, 302-314.
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Hou, F., Sun, L., Zheng, H., Skaug, B., Jiang, Q.X., and Chen, Z.J. (2011). MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response. Cell 146, 448-461.
Jiang, X., Kinch, L., Brautigam, C.A., Chen, X., Du, F., Grishin, N., Chen, Z.J. (2012) Ubiquitin-induced oligomerization of RIG-I and MDA5 activates antiviral innate immune response. Immunity 36, 959-973.
Liu, S., Chen, J., Cai, X., Wu, J., Chen, X., Wu, Y-T., Sun, L., and Chen, Z.J. (2013) MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. eLife 2:e00785
Xu, H., He, X., Zheng, H., Huang, L.J., Hou, F., Yu, Z., de la Cruz, M.J., Borkowski, B., Zhang, X., Chen, Z.J., and Jiang, Q.X. (2014) Structural basis for the prion-like MAVS filaments in antiviral innate immunity. Elife. 3:e01489.
Cai, X., Chen, J., Xu, H., Liu, S., Jiang, Q.X., Halfmann, R., and Chen, Z.J. (2014) Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation. Cell. 156(6):1207-22.
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y., Grishin, N., and Chen, Z.J. (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING and TRIF induces IRF3 activation. Science 347, aaa2630.
陈教授团队也对细胞质DNA如何诱导I型干扰素感兴趣，这对于抵御DNA病毒和细胞内细菌的免疫防御非常重要。此外，细胞质自身DNA的不适当存在可能会引发自身免疫疾病。陈教授团队发现富含AT的DNA由RNA聚合酶III转录成携带5’-三磷酸基团的RNA，这些RNA通过RIG-I通路诱导干扰素。然而，大多数DNA通过一种与序列无关的方式诱导干扰素，这种机制依赖于内质网蛋白STING（也称为MITA）。陈教授团队最近表明，在刺激后，STING招募TBK1和IRF3，从而特异性地由TBK1对IRF3进行磷酸化。
Chiu, Y.H., Macmillan, J.B., and Chen, Z.J. (2009). RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576-591.
Tanaka, Y., and Chen, Z.J. (2012). STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway. Science Signaling 5, ra20.
陈教授团队鉴定出了cGAS，它能够直接与细胞质DNA结合，形成二聚体，并从GTP和ATP合成cGAMP，该发现也让陈教授团队获得2024年拉斯克奖基础医学研究奖。具有混合磷酸二酯键的cGAMP与STING高亲和力结合，并诱导STING的构象变化和干扰素的表达。陈教授团队生成了cGAS敲除的小鼠和细胞系，利用这些试剂，陈教授团队发现cGAS-cGAMP通路对于抗DNA病毒、逆转录病毒和细菌的免疫应答至关重要。此外，陈教授团队发现cGAS还在DNA酶缺乏小鼠中导致的严重炎症中发挥作用，这表明cGAS也可以被自身DNA激活，并可能导致一些狼疮患者的炎症。
Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., Chen Z.J. (2012) Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA. Science 339, 826-830.
Sun, L., Wu, J., Du, F., Chen, X., Chen, Z.J. (2012) Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway. Science 339, 786-791.
Zhang, X., Shi, H., Wu, J., Zhang, X., Sun, L., Chen, C., and Chen, Z.J. (2013) Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51:226-235.
Gao, D., Wu, J., Wu, Y-T., Du, F., Aroh, C., Yan, N., Sun, L., and Chen, Z.J. (2013) Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses. Science 341:903-906.
Li, X.D., Wu, J., Gao, D., Wang, H., Sun, L., and Chen, Z.J. (2013) Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects. Science 341(6152):1390-4.
Zhang, X., Wu, J., Du, F., Xu, H., Sun, L., Chen, Z., Brautigam, C.A., Zhang, X., and Chen, Z.J. (2014) The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 6(3):421-30.
Collins, A.C., Cai, H., Li, T., Franco, L.H., Li, X-D., Nair, V.R., Scharn, C.R., Stamm, C.E., Levine, B., Chen, Z.J*., Shiloh, M.U*. (2015) Cyclic GMP-AMP synthase is an innate immune sensor of Mycobacterium tuberculosis DNA. Cell Host Microbe 17, 820-828. *co-corresponding author
Gao, D., Li, T., Li, X-D., Chen, X., Li, Q-Z., Wight-Carter, M., and Chen, Z.J. (2015) Activation of Cyclic GMP-AMP Synthase by Self DNA Causes Autoimmune Diseases. Proc Natl Acad Sci U S A. 112, E5699-705.
陈教授团队最近关于共生细菌的研究使陈教授团队发现TLR13在检测细菌23S核糖体RNA（rRNA）中的作用。令人惊讶的是，陈教授团队发现TLR13能够识别位于23S rRNA活性位点附近约13个核苷酸的特定序列，该位点催化肽键合成。因此，与其他检测微生物成分“模式”的先天免疫传感器不同，TLR13能够以极高的序列特异性检测细菌RNA。IRF5是一种对于多个TLR免疫信号传导至关重要的转录因子。陈教授团队最近发现，IKKβ通过磷酸化IRF5诱导其二聚化并核转位。
Li, X. and Chen, Z.J. (2012). Sequence specific detection of bacterial 23S ribosomal RNA by TLR13. eLife 1, e00102
Ren, J., Chen, X., and Chen, Z.J. (2014) IKKbeta Is An IRF5 Kinase that Instigates Inflammation. Proc Natl Acad Sci USA 111, 17438–17443.
