Research
In our lab, we are interested in unraveling the intricate regulation and crosstalk of cytokine signaling pathways. Our focus is on understanding the immune responses in the pathogenesis of several human diseases, in particular secondary bacterial lung infections and fatty liver disease.
To address these issues, we take a comprehensive approach, combining studies in human and mouse cells and in vivo models. A cornerstone of our investigations is the study of protein-protein interactions - a fundamental mechanism that mediates and diversifies cytokine signaling in different cell types and under different physiological conditions.
To make advances in this area, we've developed innovative methods to identify novel binding partners of our proteins of interest. In addition, we collaborate with cryo-electron microscopy (Cyro-EM) to unravel the structural information of the identified complexes. Our overall goal is not only to unravel the underlying pathological mechanisms, but also to translate these findings into novel therapeutic strategies. These strategies are aimed at counteracting the dysregulation of immune responses in various human diseases, paving the way for innovative approaches in healthcare.
Biography
Education & Professional Highlights
Research
The Wang Lab studies how protein interactions regulate cytokine signaling in inflammatory diseases
STAT2 in human diseases
The focus of research in our laboratory is to understand the regulation and function of the JAK-STAT pathway in inflammatory diseases. Signal transducer and activator of transcription 2 (STAT2) is a key transcription factor that initiates interferon (IFN) signaling and plays a critical role in viral clearance. We aimed to uncover novel regulations and non-canonical activities associated with STAT2. Using cell and animal models, as well as clinical samples, our recent findings have provided new insights into the involvement of STAT2 in liver lipid metabolism and infection-induced lung injury. The ultimate goal is to use this knowledge to develop innovative therapeutic modulators targeting the pathway in treating inflammation and infectious diseases.
Protein-protein interactions
Protein-protein interactions (PPIs) are fundamental to all biological processes. Our group has developed Insertional Protein Interactome Analysis (IPIA), a next-generation protein interactomics approach. Unlike any existing method, IPIA uses an engineered lentivirus to effortlessly generate a pool of cells. Each cell expresses a random protein from the genome and emits a fluorescent signal when it interacts with the protein of interest. IPIA establishes a versatile multi-omics platform that collaborates advanced technologies, including flow cytometry, next-generation sequencing (NGS), mass spectrometry (MS), and cryo-electron microscopy (cryo-EM). This platform aims to provide an advanced understanding of the properties and functions of the PPI network at a high-resolution, single-cell level. The overall goal is to elucidate downstream pathogenic mechanisms and identify novel pharmaceutical targets.
Our Team
Selected Publications
1. Wang C, Nan J, Holvey-Bates E, Chen X, Wightman S, Latif M-B, Zhao J, Li X, Sen GC, Stark GR, Wang Y. STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage. Proceedings of the National Academy of Sciences. 2023;120(16):e2216953120.
2. Song Q, Datta S, Liang X, Xu X, Pavicic P, Zhang X, Zhao Y, Liu S, Zhao J, Xu Y. Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization. Cellular & Molecular Immunology. 2023;20(2):143-57.
3. Philips RL, Wang Y, Cheon H, Kanno Y, Gadina M, Sartorelli V, Horvath CM, Darnell JE, Stark GR, O’Shea JJ. The JAK-STAT pathway at 30: Much learned, much more to do. Cell. 2022;185(21):3857-76.
4. Wightman SM, Alban TJ, Chen X, Lathia JD, Wang Y, Stark GR. Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM. Translational Oncology. 2021;14(11):101192.
5. Wang Y, Song Q, Huang W, Lin Y, Wang X, Wang C, Willard B, Zhao C, Nan J, Holvey-Bates E. A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses. Cell Research. 2021;31(2):206-18.
6. Zhu N, Zhang J, Du Y, Qin X, Miao R, Nan J, Chen X, Sun J, Zhao R, Zhang X. Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer. Proceedings of the National Academy of Sciences. 2020;117(26):15047-54.
7. Davuluri G, Giusto M, Chandel R, Welch N, Alsabbagh K, Kant S, Kumar A, Kim A, Gangadhariah M, Ghosh PK. Impaired ribosomal biogenesis by noncanonical degradation of β-catenin during hyperammonemia. Molecular and Cellular Biology. 2019;39(16):e00451-18.
8. Wang Y, Stark GR. A new STAT3 function: pH regulation. Cell Research. 2018;28(11):1045-
9. Stark GR, Cheon H, Wang Y. Responses to cytokines and interferons that depend upon JAKs and STATs. Cold Spring Harbor perspectives in biology. 2018;10(1):a028555.
10. Song Z, Ren D, Xu X, Wang Y. Molecular cross‐talk of IL‐6 in tumors and new progress in combined therapy. Thoracic Cancer. 2018;9(6):669-75.
11. Nan J, Wang Y, Yang J, Stark GR. IRF9 and unphosphorylated STAT2 cooperate with NF-κB to drive IL6 expression. Proceedings of the National Academy of Sciences. 2018;115(15):3906-11.
12. Liao L, Liu ZZ, Langbein L, Cai W, Cho E-A, Na J, Niu X, Jiang W, Zhong Z, Cai WL. Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer. Elife. 2018;7:e37925.
13. Wang Y, Nan J, Willard B, Wang X, Yang J, Stark GR. Negative regulation of type I IFN signaling by phosphorylation of STAT 2 on T387. The EMBO journal. 2017;36(2):202-12.
14. Nan J, Du Y, Chen X, Bai Q, Wang Y, Zhang X, Zhu N, Zhang J, Hou J, Wang Q. TPCA-1 is a direct dual inhibitor of STAT3 and NF-κB and regresses mutant EGFR-associated human non–small cell lung cancers. Molecular cancer therapeutics. 2014;13(3):617-29.
15. Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proceedings of the National Academy of Sciences. 2013;110(42):16975-80.
16. Chen X, Du Y, Nan J, Zhang X, Qin X, Wang Y, Hou J, Wang Q, Yang J. Brevilin A, a novel natural product, inhibits janus kinase activity and blocks STAT3 signaling in cancer cells. PLoS One. 2013;8(5):e63697.
17. He J, Shi J, Xu X, Zhang W, Wang Y, Chen X, Du Y, Zhu N, Zhang J, Wang Q. STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway. Journal of biosciences. 2012;37:243-57.
18. Stark GR, Wang Y, Lu T. Lysine methylation of promoter-bound transcription factors and relevance to cancer. Cell research. 2011;21(3):375-80.
19. Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B, Chance MR, Chen X, Du Y, Wang Y. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proceedings of the National Academy of Sciences. 2010;107(50):21499-504.