WU Xuefeng
Email: xuefengwu@shsmu.edu.cn
Tel: 021-63846590-776684
Research Field:
Elucidating the metabolic regulatory network of immune cells, particularly the organelle homeostasis and stress response pathways in T cells and Treg cells. Based on previously established research platforms for endocytosis/autophagy, endoplasmic reticulum stress, and reactive oxygen species (ROS)/oxidative stress, we are screening for proteins that regulate endocytosis/autophagic flux, stress responses, and ROS homeostasis (using the ROS reporter Hyperion mouse) in immune cells and validate their functional roles.
Uncovering the regulatory and intervention mechanisms of immune cell function. Through unbiased screening approaches (such as genome-wide CRISPR screening), we are identifying regulators of T/Treg cell functions—including CD8⁺ T cell cytotoxicity or exhaustion, Treg suppressive function, CAR-T cell trogocytosis, and dendritic cell migration. Tools such as the CCR7-EGFP reporter mouse generated earlier will be utilized in these screens.
Developing novel targets and efficacy-enhancing strategies for immunotherapy. Building on prior discoveries of immune-modulatory targets (e.g., VPS33B, TMED4, Ubc13, STK40), we are employing antisense oligonucleotides, small molecules, and antibody-based agents for targeted intervention. The effects of these interventions on enhancing antitumor immunity and ameliorating autoimmune diseases will be evaluated using immune cell therapies (e.g., chimeric antigen receptor CAR-T/Treg cells). These studies will be further extended to newly identified targets from the aforementioned screens that regulate immune cell metabolism and function. Finally, adopting a disease-oriented approach, we will collaborate with clinicians to screen for therapeutic response and diagnostic biomarkers from clinical cohorts, conduct mechanistic experiments to confirm their functions, and focus on biomarkers (including autoantibodies) in the serum of patients with refractory rheumatoid arthritis, rheumatoid arthritis-associated interstitial lung disease, and sepsis. These efforts will address clinically relevant challenges, advance mechanistic understanding, and enable translational applications. We have established close collaborations with relevant clinical teams, aiming to integrate basic and clinical research to lay a solid foundation for the development of immunotherapeutic drugs.
Personal Introduction:
Xuefeng Wu, Ph.D., Principal Investigator, Doctoral Supervisor at Shanghai Jiao Tongs University School of Medicine/Shanghai Institute of Immunology. He is a recipient of the National Youth Talent Program for Overseas High‑Level Talents. He earned his Bachelor’s and Master’s degrees from Nankai University, and a Ph.D. in Immunology with Professor Shao-Cong Sun at Pennsylvania State University, USA. He completed postdoctoral training at the University of Texas MD Anderson Cancer Center with Professor Shao-Cong Sun and University of California, San Diego with Professor Michael Karin. He previously served as a Senior Scientist at a leading U.S. pharmaceutical company, where he focused on the development of nucleic acid therapeutics for tumor immunotherapy. He has presided over projects supported by the Shanghai Municipal Science and Technology Commission and the National Natural Science Foundation of China, participated in three National Key R&D Programs. His research group investigates the regulation of organelle homeostasis and stress responses in T/Treg cells, and their mechanisms and applications in autoimmune diseases and tumor immunity. To date, he has published over 40 research articles, including the following as corresponding (or co-corresponding) author: Journal of Clinical Investigation (2024), Science Advances (2024), FASEB J. (2024), Cell Reports (2022), Nature Communications (2021), Journal of Immunology (2021 & 2023), European Journal of Immunology (2022 & 2024), Theranostics (2021).
Scientific Research Projects:
Funding Source: National Natural Science Foundation of China
Study on the role and mechanism of targeting endoplasmic reticulum stress response protein TMED4 in enhancing the anti-tumor immune function of CD8+ T cells
32571064, 2026-2029，Project Leader
Funding Source: National Key Research and Development Program of China
Systematic Study on the Diagnosis and Treatment Patterns of Rheumatoid Arthritis with Integrated Traditional Chinese and Western Medicine
2024YFC3506205,2025-2029, Key Participant.
Funding Source:Natural Science Foundation of Shanghai
The Ubc13-NLRP3 Inflammasome Signaling Axis in Sepsis: Regulation of Host Response and Its Role in Early Diagnosis and Intervention
24ZR1492400,2024-2027,Project Leader.
Funding Source: National Key Research and Development Program of China
Precision diagnosis and treatment and application of severe infectious diseases in children
2021YFC2701800, 2022-2024，Key Participant.
Funding Source:Organization Department of the CPC Central Committee
Overseas high-level talents Youth Project,2017-2020
Publications:
Sun S, Ni J, Liu J, Tan J, Jin R, Li H, Wu X*. Ubiquitin-Conjugating Enzyme Ubc13 in Macrophages Suppresses Lung Tumor Progression Through Inhibiting PD-L1 Expression. Eur J Immunol. 2024 Dec 23:e202451118. doi: 10.1002/eji.202451118. Epub ahead of print. PMID: 39711265.
Jiang Z, Wang H, Wang X, Duo H, Tao Y, Li J, Li X, Liu J, Ni J, Wu EJ, Xiang H, Guan C, Wang X, Zhang K, Zhang P, Hou Z, Liu Y, Wang Z, Su B, Li B, Hao Y*, Li B*, Wu X*. TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models. J Clin Invest. 2024 Oct 31:e179874.doi: 10.1172/JCI179874. Epub ahead of print. PMID: 39480507.
Tao Y, Jiang Z, Wang H, Li J, Li X, Ni J, Liu J, Xiang H, Guan C, Cao W, Li D, He K, Wang L, Hu J, Jin Y, Liao B*, Zhang T*, and Wu X*. Pseudokinase STK40 promotes Th1 and Th17 cell differentiation by targeting FOXO transcription factors. Sci Adv. 2024 Nov 22;10(47):eadp2919. doi: 10.1126/sciadv.adp2919. Epub 2024 Nov 20. PMID: 39565845.
Wen Z, Yuan T, Liu J, Wang D, Ni J, Yan X, Tang J*, Tang J*, Wu X*, Wang Z*. Atg16l2 augments Nlrc4 inflammasome activation by facilitating NAIPs-NLRC4 association. Eur J Immunol. 2024 Aug 22:e2451078. doi: 10.1002/eji.202451078. PMID: 39175123.
Li Z, Zhao J, Wu Y, Fan S, Yuan H, Xia J, Hu L, Yang J, Liu J, Wu X*, Lin R*, Yang L*. TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation. FASEB J. 2024 Feb 29;38(4):e23491.PMID: 38363556.
Cao W, Liu J, Jiang Z, Tao Y, Wang H, Li J, Ni J, Wu X. Tumor Suppressor Adenomatous Polyposis Coli Sustains Dendritic Cell Tolerance through IL-10 in a β-Catenin-Dependent Manner. J Immunol. 2023 Mar 31:ji2300046. PMID: 37000474.
Geng Y, Li L, Yan J, Liu K, Yang A, Zhang L, Shen Y, Gao H, Wu X, Noth I, Huang Y, Liu J, Fan X. PEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis. Nat Commun. 2022 Nov 19;13(1):7114. PMID: 36402779
Xiang H, Tao Y, Jiang Z, Huang X, Wang H, Cao W, Li J, Ding R, Shen M, Feng R, Li L, Guan C, Liu J, Ni J, Chen L, Wang Z, Ye Y, Zhong Q, Liu J, Zou Q, Wu X*. Vps33B controls Treg cell suppressive function through inhibiting lysosomal nutrient sensing complex-mediated mTORC1 activation. Cell Rep. 2022 Jun 14;39(11):110943. PMID: 35705052.
Wang D#, Yuan T#, Liu J#, Wen Z, Shen Y, Tang J, Wang Z*, Wu X*. ATG16L2 inhibits NLRP3 inflammasome activation through promoting ATG5-12-16L1 complex assembly and autophagy. Eur J Immunol. 2022 Apr 15. PMID: 35426127
Kim MC#, Borcherding N#, Ahmed KK#, Voigt AP#, Vishwakarma A, Kolb R, Kluz PN, Pandey G, De U, Drashansky T, Helm EY, Zhang X, Gibson-Corley KN, Klesney-Tait J, Zhu Y, Lu J, Lu J, Huang X, Xiang H, Cheng J, Wang D, Wang Z, Tang J, Hu J, Wang Z, Liu H, Li M, Zhuang H, Avram D, Zhou D, Bacher R, Zheng SG, Wu X*, Zakharia Y*, Zhang W*. CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells. Nat Commun. 2021; 12(1):5764. PMID: 34599187
Ni J, Guan C, Liu H, Huang X, Yue J, Xiang H, Jiang Z, Tao Y, Cao W, Liu J, Wang Z, Wang Y*, Wu X*. Ubc13 promotes K63-linked poly-ubiquitination of NLRP3 to activate inflammasome. Journal of Immunology 2021; 206(10):2376-2385. PMID: 33893171
Guan C, Huang X, Yue J, Xiang H, Shaheen S, Jiang Z, Tao Y, Tu J, Liu Z, Yao Y, Yang W, Hou Z, Liu J, Yang XD, Zou Q, Su B, Liu Z, Ni J*, Cheng J*, Wu X*. SIRT3-mediated deacetylation of NLRC4 promotes inflammasome activation. Theranostics 2021; 11(8):3981-3995. PMID: 33664876
Zhu Q, Yu T, Gan S, Wang Y, Pei Y, Zhao Q, Pei S, Hao S, Yuan J, Xu J, Hou F, Wu X, Peng C, Wu P, Qin J, Xiao Y. TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination. J Exp Med. 217(7):e20192083. (2020). PMID: 32324863
Yang XD, Li W, Zhang S, Wu D, Jiang X, Tan R, Niu X, Wang Q, Wu X, Liu Z, Chen LF, Qin J, Su B. PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome. EMBO J. 39 (2):e102201. (2020) PMID: 31762063
Wang T, Cao Y, Zheng Q, Tu J, Zhou W, He J, Zhong J, Chen Y, Wang J, Cai R, Zuo Y, Wei B, Fan Q, Yang J, Wu Y, Yi J, Li D, Liu M, Wang C, Zhou A, Li Y, Wu X, Yang W, Chin YE, Chen G, Cheng J. SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism. Mol Cell. 22; 75(4):823-834 (2019). PMID: 31302001
Huang X, Zuo Y, Wang X, Wu X, Tan H, Fan Q, Dong B, Xue W, Chen GQ, Cheng J. SUMO-Specific Protease 1 Is Critical for Myeloid-Derived Suppressor Cell Development and Function. Cancer Res. 79(15):3891-3902. (2019). PMID: 31186231
Yu X, Lao Y, Teng XL, Li S, Zhou Y, Wang F, Guo X, Deng S, Chang Y, Wu X, Liu Z, Chen L, Lu LM, Cheng J, Li B, Su B, Jiang J, Li HB, Huang C, Yi J, Zou Q. SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Nat Commun. 9(1):3157. (2018) PMID: 30089837
Todoric J#, Antonucci L#, Di Caro G#, Li N#, Wu X, Lytle NK, Dhar D, Banerjee S, Fagman JB, Browne CD, Umemura A, Valasek MA, Kessler H, Tarin D, Goggins M, Reya T, Diaz-Meco M, Moscat J, Karin M. Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Cancer Cell. 32(6):824-839.e8. (2017) PMID: 29153842
Kaneda MM, Messer KS, Ralainirina N, Li H, Leem C, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA. PI3Kγ is a molecular switch that controls immune suppression. Nature 2016 Sep 19. doi: 10.1038/nature19834. [Epub ahead of print] PMID: 27642729
Wu X, M Karin. Emerging roles of Lys63-linked polyubiquitylation in immune responses. Immunol Rev. 266(1):161-74. (2015) PMID: 26085214
Jo M, Schmidt J, Zhou T, Wu X, Crosby J, Brand E, Kim Y, and Macleod R. Strong pharmacological activity of locally administered next-generation antisense oligonucleotides (ASOs) in orthotopic lung cancer mouse models. Journal of Thoracic Oncology. 11(25): S26 (2015). DOI: http://dx.doi.org/10.1016/j.jtho.2015.12.043
Inokuchi-Shimizu S, EJ Park, YS Roh, L Yang, B Zhang, J Song, S Liang, M Pimienta, K Taniguchi, X Wu, K Asahina, W Lagakos, MR Mackey, S Akira, MH Ellisman, DD Sears, JM Olefsky, M Karin, DA Brenner, E Seki. TAK1-Mediated Autophagy and Fatty Acid Oxidation Prevent Hepatosteatosis and Tumorigenesis. J Clin Invest. 124(8):3566-78. (2014) PMID: 24983318
Charlaftis N, Suddason T, X Wu, M Karin and E Gallagher. The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. EMBO J. 33(21):2581-96. (2014) PMID: 25260751
Zhang H, H Hu, N Greeley, J Jin, A Matthews, E Ohashi, M Caetano, H Li, X Wu, P Mandel, J McMurray, SJ Moghaddam, S-C Sun, S. Watowich. STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13. Nature Communications 2014 Dec 15; 5:5798. doi: 10.1038/ncomms6798. (2014) PMID: 25503582
Wu X, W Zhang, J Font-Burgada, T Palmer, AS Hamil, SK Biswas, M Poidinger, N Borcherding, Q Xie, LG Ellies, N Lytle, LW Wu, J Yang, SF Dowdy, T Reya, M Karin. Ubiqutin-conjugating Enzyme Ubc13 Controls Breast Cancer Metastasis through a TAK1-p38 MAP Kinase Cascade. PNAS (2014) 111(38): 13870-5. PMID: 25189770 Highlighted in International, National and Regional Media including Union-Tribute San Diego Sept 7, 2014; and Science Signaling Editors’ Choice 7 (345), ec264.
Li N, Wu X, Holzer RG, Lee JH, Todoric J, Park EJ, Ogata H, Gukovskaya AS, Gukovsky I, Pizzo DP, Vandenberg S, Tarin D, Atay C, Arkan MC, Deerinck TJ, Moscat J, Diaz-Meco M, Dawson D, Erkan M, Kleeff J, Karin M. Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice. J Clin Invest. 123(5):2231-43. (2013) PMID: 23563314
Zhang W, Tan W, Wu X, Poustovoitov M, Strasner A, Li W, Borcherding N, Ghassemian M, Karin M. A NIK-IKKα Module Expands ErbB2-Induced Tumor-Initiating Cells by Stimulating Nuclear Export of p27/Kip1. Cancer Cell. 23(5):647-59. (2013) PMID: 23602409
Mancino A, Habbeddine M, Johnson E, Luron L, Bebien M, Memet S, Fong C, Bajenoff M, Wu X, Karin M, Caamano J, Chi H, Seed M, Lawrence T. I kappa B kinase alpha (IKKα) activity is required for functional maturation of dendritic cells and acquired immunity to infection. EMBO J. 32(6):816-28. (2013) PMID: 23422957
Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M, Cheng X, Sun SC. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol. 13: 481-490 (2012) PMID: 22484734
Wu X#, Zhang M# and Sun S-C. Mutual regulation between deubiquitinase CYLD and Retroviral Oncoprotein Tax. Cell & Bioscience 2011 Aug 8; 1(1):27. PMID: 21824392
Hu H#, Wu X#, Jin W, Chang M, Cheng X and Sun S-C. Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development. PNAS 2011 Aug 2; 108(31):12827-32. Epub 2011 Jul 18. [* co-first author] PMID: 21768353
Zhang M, Lee AJ, Wu X, Sun SC. Regulation of antiviral innate immunity by deubiquitinase CYLD. Cell Mol Immunol. 8(6):502-4 (2011). PMID: 21946435
Xu G, Y-C Lo, Q Li, G Napolitano, Wu X, X Jiang, Karin M and Wu H. Crystal structure of the inhibitor of κB kinase β (IKKβ). Nature 472 (7343):325-30 (2011). PMID: 21423167
Lee A#, Wu X#, H Cheng, X Zhou, X Cheng, and S-C Sun. CARMA1 regulation of Treg development involves modulation of IL-2 receptor signaling. J. Biol Chem. 2010 Mar25. 285(21): 15696-703 (2010). PMID: 20233721
Wu X, M Yamamoto, S Akira, and S-C Sun. Regulation of hematopoiesis by the K63-specific ubiquitin-conjugating enzyme Ubc13. PNAS 106 (49): 20836-41 (2009). PMID: 19926860
Zhang M#, Wu X#, AJ Lee, W Jin, M Chang, A Wright, T Imaizumi, and S-C Sun. Regulation of IKK-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem. 283(27): 8621-6 (2008). PMID: 18467330
Wu X, S-C Sun. Retroviral oncoprotein Tax deregulates NF-κB by activating Tak1 and mediating Tak1-IKK physical association. EMBO Rep. 8(5): 510-5 (2007). PMID: 17363973
Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med. 204(6): 1475-85 (2007). PMID: 17548520
Jin W, Reiley WR, Lee AJ, Wright A, Wu X, Zhang M, Sun SC. Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells. J Biol Chem. 282(21): 15884-93 (2007). PMID: 17392286
Babu G, Waterfield M, Chang M, Wu X, Sun SC. Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells. J Biol Chem. 281(20): 14041-7 (2006). PMID: 16565081
Babu GR, Jin W, Norman L, Waterfield M, Chang M, Wu X, Zhang M, Sun SC. Phosphorylation of NF-kappaB1/p105 by oncoprotein kinase Tpl2: implications for a novel mechanism of Tpl2 regulation. Biochim Biophys Acta. 1763(2): 174-81 (2006). PMID: 16448710
Reiley W, M Zhang, Wu X, E Granger, and S-C Sun. Regulation of the deubiquitinating enzyme CYLD by IKKγ-dependent phosphorylation. Mol. Cell. Biol. 25(10): 3886-95 (2005). PMID: 15870263
Abdul-Kareem AR, Sheng C, Shi, M, An C, Wu X, Li D and Du R. Isolation and Characterization of a Salt-induced Transcript from Halophyte Spartina Anglica Using DDRT-PCR. Acta Scientiarum Naturalium Universitatis Nankaiensis (Natural Science Edition) 36 (2) 8-14 (2003).
Ye M, Sheng C, Shi M, An C, Ji J, Wu X, Du R and Li D. Detection of Potato Spindle Tuber Viroid by Single-enzyme RT-PCR. Acta Agriculturae Boreali-Sinica 17 (1) 41-45 (2002).
Ji J, Sheng C, Shi M, An C, Wu X, Li D and Du R. A Study on the Transformation of Wheat with Salt-tolerant Gene HVA1 by Method Deflating Pollen Tube. Journal of Triticeae Crops 22(2): 10-13 (2002).