Hu & Zhang Lab
The State Key Laboratory of Biotherapy Si-Chuan University

Research field

Function of ubiquitination in signaling pathways involved inimmune system

Ubiquitination is one major post-translational modification, which leads to the degradation of target protein, or forming signaling complex to affect downstream signaling events. This process is balanced by ubiquitin E1/E2/E3 enzyme complex that conjugates ubiquitin to their substrate,and deubiquitinase (DUB) which removes ubiquitin chain from target protein.

Ubiquitination plays critical roles in numerous signaling pathways, including NF-kB, TLRs, RIG1, STING, TCR/BCR etc which control the immune response. Previously, we identified a new DUB, Otud7b as a key regulator of non-canonical NF-kB pathway by targeting TRAF3. In vivo study indicated Otud7b controlled the lymphoid organ development, intestinal immune response aganist bacterial infection and antibody production (Nature 2013). We will continue to work on the function of Otud7b in regulation immune homeostasis.

Non-canonical NF-kB in immune system.

NF-kB has been discovered for nearly 30 years, which consists a family oftranscription factors that control almost all the stress and infectionresponse. Based on the activation mechanism, NF-kB pathway is divided intocanonical and non-canonical NF-kB pathways. Canonical NF-kB is activated by variousstimuli and the transcription activity depends on the phosphorylation andformation of IKKs complex and degradation of IkB. The RelA/p50 dimer will bereleased and translocate into nucleus to activation gene expression. Meanwhile,the activation of non-canonical NF-kB is only induced through TNF receptorsuper family (TNFRSF). The engagement of TNFRSF and its ligands triggers thedegradation of TRAF3, resulting in liberating and accumulation of NIK. Then NIKactivates IKKa and causes the phosphorylation and processing of p100 into p52.RelB/p52 dimer will translocate into nucleus for target gene expression.

In immune system, non-canonical NF-kB has important functions, such as in B-celldevelopment and survival, lymphoid organ development, etc. We reported thatnon-canonical NF-kB is critical for ICOSL expression in B-cell, which provides supportivesignaling through ICOSL-ICOS to T cell, for Tfh (follicular T help cell) developmentand humoral immune response (PNAS, 2010).

In the study of function of TRAF3 in Treg cell, we demonstrated a new mechanism by which TRAF3 regulated TCR activated ERK-AP1 pathway and ICOS expression in Treg. TRAF3 deficient Treg cell have defected Tfr (follicular regulatory T cell) development and suppressive function (JEM, 2014).

We will further investigate the function of non-canonical NF-kB pathway in immune system, especially in mucosal immunity and immune homeostasis.


1.         Hongbo Hu, George Brittain, Jae-Hoon Chang, Nahum Puebla-Osorio, Jin Jin, AnnaZal, Yichuan, Xiao, Xuhong Cheng, Mikyoung Chang, Yang-Xin Fu, Tomasz Zal,Chengming Zhu, and Shao-Cong Sun. Otud7b controls noncanonical NF-kB activationvia deubiquitination of TRAF3. Nature. 2013 Feb 21;494(7437):371-4.

2.         Hongbo Hu, Hui Wang, Yichuan, Xiao, Jin, Jin, Jae-Hoon Chang,Qiang Zou, Xiaoping Xie, Xuhong Cheng, Shao-Cong Sun. Otud7b facilitates T cellactivation and inflammatory response by regulating Zap70 ubiquitination. Journalof Experiment Medicine. 2016. Feb. 22. Pii :jem20151426.

3.         Hongbo Hu, Shao-Cong Sun. Ubiquitin Signaling in Immune Response. Cell Research. 2016:1-27

4.    Jin Jin,Xiaoping Xie, Yichuan Xiao, Hongbo Hu,Qiang Zou, Xuhong Cheng, Shao-Cong Sun. Epigenetic regulation of IL-12/IL-23gene expression and autoimmune response by deubiquitinase Tradid.NatureImmunology, 2016. 17(3):259-68.

5.         Jae-HoonChang, Hongbo Hu*, Jin Jin,Nahum Puebla-Osorio, Yichuan Xiao, Robert Brink, Stephen E Ullrich, andShao-Cong Sun. TRAF3 regulates the effector function of regulatory T cells andhumoral immune responses. Journal of Experimental Medicine.2014 211:137-151 *Co-first author.

6.         YanchuanLi, Hui Wang, Xiaofei Zhou, Xiaoping Xie, Xiang Chen, Zuliang Jie, Qiang Zou, HongboHu, Lele Zhu, Xuhong Cheng, Hans Brightbill, Lawren Wu, Linfang Wang, Shao-CongSun. Cell intrinsic role of NF-kappaB-inducing kinases in regulating Tcell-medicated immune response and autoimmune response. Scientific Report. 2016, 6:22115| DOI: 10.1038/srep22115

7.         Qiang Zou,Jin Jin, Yichuan Xiao, Xiaofei Zhou, HongboHu, Xuhong Cheng, Nasser Kazimi, Stephen Ullrich, Shao-Cong Sun. T-cellintrinsic USP15 deficiency promotes excessive IFN-gamma production and animmunosuppressive tumor microenvironment in MAC-induced fibrosarcoma. CellReport. 2015, Dec 22;13(11):2470-9. doi:10.1016/j.celrep.2015.11.046

8.         Qiang Zou,Jin Jin, Yichuan Xiao, Hongbo Hu,Zuliang jie, Xiaoping Xie, Yichuan Li, Xuhong Cheng, Shao-Cong Sun. T celldevelopment involves TRAF3IP3-mediated ERK signaling in the Golgi. Journalof Experimental Medicine, 2015 Jul 27;212(8):1323-36. doi:10.1084/jem.20150110. Epub 2015 Jul 20.

9.         Yichuan Xiao, Jin Jin, Qiang Zou, Hongbo Hu, Xuhong Cheng,Shao-Cong Sun. Peli negatively regulates type I interferon induction and antiviral immunity in the CNS. Cell&Bioscience, 2015 Jun 24;5:34. doi:10.1186/s13578-015-0024-z.

10.      Jae-Hoon Chang, Hongbo Hu, Shao-Cong Sun. Survival and maintenance of regulatoryT-cell require the kinase TAK1. Cellular and Molecular Immunology. 2015 Sep;12(5):572-9. doi:10.1038/cmi.2015.27.

11.      Jin Jin,Yichuan Xiao, Hongbo Hu,Qiang Zou, Yanchuan Li, Yanpan Gao, Wei Ge, Xuhong Cheng and Shao-Cong Sun.Proinflammatory TLR signaling is regulated by a TRAF2-dependent proteolysismechanism in macrophages. Nature Communications. 2015 Jan7;6:5930. doi: 10.1038/ncomms6930

12.      Huiyuan Zhang,Hongbo Hu, Nathaniel Greeley,Jin Jin, Allison J. Matthews, Erika Ohashi, Mauricio S. Caetano, Haiyan S. Li,Xuefeng Wu, Pijus K. Mandal, John S. McMurray, Seyed Javad Moghaddam, Shao-CongSun, Stephanie S. Watowich. Role for STAT3 in inflammation: regulation of theubiquitin-conjugating (E2) enzyme UBC13. Nature Communications. 2014 Dec15;5:5798. doi: 10.1038/ncomms6798

13.      Yichuan,Xiao, Jin Jin, Mikyoung Chang, Mako Nakaya, Hongbo Hu, Qiang Zou, Xiaofei, Zhou, George C. Brittain,Xuhong Cheng, Shao-Cong Sun. TPL2 medicates autoimmune inflammation throughactivation of TAK1 axis of IL-17 signaling. Journal of Experimental Medicine.2014 doi: 10.1084/jem.20132640

14.      Qiang Zou,Jin Jin, Hongbo Hu, HaiyanLi, Simona Romano, Yichuan Xiao, Mako NAkaya, Xiaofei Zhou, Xuhong Cheng,Peirong Yang, Guillernima Lozano, Chengming Zhu ,Stephanine S. Watowich,Stephen Ullrich, Shao-Cong Sun. USP15 stabilizes MDM2 to mediate cancer cellsurvival and inhibit autitumor T-cell response. Nature Immunology, 2014,doi:10.1038/ni.2885

15.      Jin Jin, Hongbo Hu, Haiyuan Li, Jiayi Yu,Yichuan Xiao, Qiang Zou, Xuhong Cheng, Robyn Starr, Stephanie S. Watowich andShao-Cong Sun. Non-canonical NF-kB pathway controls the production of type IInterferons in antivirual innate immunity. Immunity, 03/2014; 40(3):342-54.

16.      YichuanXiao, Jin Jin, Mikyoung Chang, Jae-Hoon Chang, Hongbo Hu, Xiaofei Zhou, George C Brittain, Xiaodong Wang,Xuhong Cheng, Shao-Cong Sun. Peli1 Promotes microglia-mediated CNS inflammationby regulating TRAF3 degradation. Nature Medicine. 2013May;19(5):595-602.

17.      Jin Jin,Yichuan Xiao, Jae-Hoon Chang, Jiayi Yu, HongboHu, George C. Brittain, Xuhong Cheng, Shao-Cong Sun. TBK1 controls IgAclass switching by negatively regulating noncanonical NF-kB signaling.Nature Immunology. 2012, 13(11):1101-9

18.      Jae-HoonChang, Yichuan Xiao, Hongbo Hu,Jin Jin, Jiayi Yu, Howard M Johnson, Shizuo Akira, Xuhong Cheng, and Shao-CongSun. UBC13 maintains the suppressive function of regulatory T cells and preventtheir conversion into effector-like T cells. Nature Immunology. (2012)May;13(5):481-90.

19.      XiaohongWang, Hui-Kai Kuo, Gregory A. Dement, Ju-Pi Li, Li-Li Chiu, Hongbo Hu, Tse-Hua Tan,Downregulation of B-cell Receptor Signaling by HPK1-induced Phosphorylation andUbiquitination of BLNK. Journal of Biological Chemistry.2012 Mar 30;287(14):11037-48

20.      Hongbo Hu, Xuefeng Wu, Wei Jin, Mikyong Chang, Xuhong Cheng and Shao-Cong Sun.Noncanonical NF-kB regulates inducible costimulator (ICOS) ligand expressionand T follicular helper cell development. Proceedings of National Academy of Sciences.2011 Aug 2; 108(31):12827-32.

21.      Shin-HengChiou Payam Shahi, Ryan T Wagner, HongboHu, Natalia Lapteva, Mamatha Seethammagari, Shao-Cong Sun, Jonathan MLevitt and David M Spencer. The E3 ligase c-Cbl regulates dendritic cellactivation. EMBO Report. (2011) 12, 971-9.

22.      KatherineL Tucker, William J. Kaiser, Angela L. Bergeron, Hongbo Hu, Jing-fei Dong, Tse-Hua Tan, Jonathan M. Gibbins.Proteomic analysis of resting and thrombin-stimulated platelets reveals thetranslocation and functional relevance of HIP-55 in platelets. Proteomics,2009, 9(18): 4340–4354

23.      Xueyan XiYang Guo, Hui Chen, Chunping Xu, Huiyuan Zhang, Hongbo Hu, Lianxian Cui, Denian Ba, and Wei He. Antigen specificity of gammadelta T cells depends primarily on theflanking sequences of CDR3delta. Journal of Biological Chemistry. 2009, 284:27449-55.

24.      Zhun Wang,Tie Zhang, Hongbo Hu, HuiyuanZhang, Zhi Yang, Lianxian Cui, Wei He. Targeting solid tumors via T cellreceptor complementarity-determining region 3δ in anengineered antibody. Cancer Letter. 2008 272:242-252.

25.      ChunpingXu, Huiyuan Zhang, Hongbo Hu*,Hongbie He, Zhun Wang, Yong Xu, Hui Chen, Wei Cao, Sumei Zhang, Lianxian Cui,Denian Ba, Wei He. gd T cells recognize tumor cells via CDR3d region. Molecular Immunology, 2007;44(4):302-10. *Co-first author.

26.      Hongbo Hu, Li L, Richard Y, Kao, Binbin Kou, Zhanguo Wang, Huiyuan Zhang, ZhiyongHao, Wayne H. Tsui, Anping Ni, Lianxian Cui, Baoxing Fan, Qian Li, Manji Sun,Wei He, Gang Liu. Screening and Identification of Linear B-cell Epitopes andEntry Blocking Peptide of Severe Acute Respiratory Syndrome (SARS) AssociatedCoronavirus Using Synthetic Overlapping Peptide Library. Journal of CombinatorialChemistry, 2005; 12 ;7(5):648-656.

27.      HuiyuanZhang, Hongbo Hu, XinxinJiang, Hongbin He, Lianxian Cui, Wei He. Membrane HSP70: the molecule triggeringgd T cells in the early stage of tumor-genesis. Immunologicalinvestigations. 2005; 34:453-468.

28.      HuabiaoChen, Jinlin Hou, Xiaodong Jiang, Shiwu Ma, Minjie Meng, Baomei Wang, MinghuiZhang, Mingxia Zhang, Xiaoping Tang, Fuchun Zhang, Tao Wan, Nan Li, Yizhi Yu, Hongbo Hu, Ruifu Yang, Wei He, Xiaoning Wang, and Xuetao Cao. Response of Memory CD8+ T Cells to Severe Acute RespiratorySyndrome (SARS) Coronavirus in Recovered SARS Patients and Healthy Individuals.Journalof Immunology. 2005; 175:591-598.