Zhenming Xu, Ph.D.

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RESEARCH

Dr. Zhenming Xu's lab conducts biomedical research that will advance the fundamental understanding of immunology, to translate our knowledge for the development of therapeutics that benefit patients, and to mentor graduate students and post-doctoral fellows towards a successful career.

Research

Key Areas

B lymphocyte activation and differentiation in the antibody response; host immune response to infection, cancer; immunoaging; Toll-like receptors and other immune receptors in B cells; intracellular membrane structures in signal transduction/integration in immunity.

Summary

Dr. Zhenming Xu's lab research focuses on the mechanisms underlying differentiation and functions of B lymphocytes in antibody responses to infectious pathogens and vaccines. These mechanisms include the nature of innate and adaptive stimuli (as produced by microbes or host cells) that can activate B cells, the modality of signal transduction pathways, and interactions of protein factors, epigenetic marks and DNA cis-elements in regulating the gene expression and targeting of molecular machineries. 

Importantly, they have characterized the modality of NF-kB activation in B cells by these stimuli and analyzed the NF-kB-dependent induction of activation-induced cytidine deaminase (AID), a genome-editing enzyme that is essential for antibody class-switching and affinity improvement but can also lead to genome-wide DNA damages when dysregulated. Their recent findings have demonstrated that Rab7, a small GTPase that localizes mainly in endosomes, plays a B cell-intrinsic role in NF-kB activation and AID induction for effective antibody responses, likely through assembly of “signalosomes” on intracellular membrane structures to strengthen signals and their specificity.

They also want to understand how B cell differentiation mechanisms are dysregulated, leading to disease conditions, and aim to explore the therapeutic potential of targeting these mechanisms. For this, we use animal models of autoimmune diseases (e.g., the life-debilitating systemic lupus) and B cell malignancies (e.g., diffused large B cell lymphoma) as well as aging mice. They also use a Rab7-specific small molecule compound to prevent or reverse B cell dysregulation in the context of lupus and B cell lymphomagenesis, and are in the process to develop compound derivatives with further enhanced affinities for their targets and decreased affinity for off-targets. These studies have high clinical relevance and will facilitate the development of new therapeutics.

Publications

Xu, Z., J. Choi, T. S. Yen, W. Lu, A. M. Strohecker, S. Govondarajan, M. Selby, D. Chien and J-H. Ou. 2001. Synthesis of a novel HCV protein by ribosomal frameshift. EMBO J. 20:3840-3848.

Xu, Z., T. S. Yen, L. Wu, C. R. Madden, W. Tan, B. L. Slagle and J-H. Ou. 2002. Enhancement of hepatitis B virus replication by its X protein in transgenic mice. J. Virol. 76:2579-2584.

Xu, Z., J. Choi, W. Lu and J-H. Ou. 2003. Hepatitis C virus F protein is a short-lived protein associated with the endoplasmic reticulum. J. Virol. 77:1578-1583.

Hu, R., J. Sheng, X. Qi, Z. Xu, S. T. T. Takahashi and A. Varshavsky. 2005. The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature 437:981-986.

Komori, A.*, Z. Xu*, X. Wu, H. Zan and P. Casali. 2006. Biased dA/dT somatic hypermutation as regulated by the heavy chain intronic iEm enhancer and 3’Ea enhancers in human lymphoblastoid B cells. Mol. Immunol. 43:1817-1826 (*equal contributors).

Xu, Z., E. J. Pone, A. Al-Qahtani, S.-R. Park, H. Zan and P. Casali. 2007. Regulation of aicda expression and AID activity: rwelevance to somatic hypermutation and class switch DNA recombination. Crit. Rev. Immunol. 27:367-397.

Park, S.-R., H. Zan, Z. Pal, J. Zhang, A. Al-Qahtani, E. J. Pone, Z. Xu, T. Mai and P. Casali. 2009. HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nat. Immunol. 10:540-550.

Xu, Z., Z. Fulop, G. Wu, E. J. Pone, J. Zhang, T. Mai, L. M. Thomas, A. Al-Qahtani, C. A. White, S.-R. Park, P. Steinacker, Z. Li, J. R. Yates, III, B. Herron, M. Otto, H. Zan, H. Fu and P. Casali. 2010. 14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nat. Struct. Mol. Biol.17:1124-1135.

Pone, E. J.*, J. Zhang*, T. Mai, C. A. White, G. Li, J. K. Sakakura, P. J. Patel, A. Al-Qahtani, H. Zan, Z. Xu* and P. Casali. 2012. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-kB pathway. Nat. Commun. 3:767, 1-12 (*equal contributors).

Xu, Z., H. Zan, E. J. Pone, T. Mai and P. Casali. 2012. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat. Rev. Immunol. 12:517-531.

Li, G., E. J. Pone, D. C. Tran, P. J. Patel, L. Dao, Z. Xu§ and P. Casali. 2012. Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination. J. Biol. Chem.287:21520-21529 (§corresponding author).

Mai T., E. J. Pone, G. Li, T. S. Lam, J. Moehlman, Z. Xu§ and P. Casali§. 2013. Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3g is mediated by NF-kB-dependent recruitment of CFP1 to the 5’-CpG-3’-rich 14-3-3gpromoter and is sustained by E2A. J. Immunol. 191:1895-1906 (§co-corresponding authors).

Li, G.*, C. A. White, T. Lam, E. J. Pone, D. C. Tran, K. L. Hayama, H. Zan, Z. Xu* and P. Casali. 2013. Combinatorial H3K9acS10ph histone modifications in IgH locus S regions target 14-3-3 adaptors and AID to specify antibody class switch DNA recombination. Cell Rep. 5:702-714(*equal contributors).

Pone E. J., Z. Lou, T. Lam, M. L. Greenberg, R. Wang, Z. Xu§ and P. Casali§. 2015. B cell TLR1/2, TLR4, TLR7 and TLR9 interact in induction of class switch DNA recombination: modulation by BCR and CD40, and relevance to T-independent antibody responses. Autoimmunity 48: 1-12 (§co-corresponding authors).

Pone E. J., T. Lam, Z. Lou, R. Wang, Y. Chen, D.-F. Liu, A. L. Edinger, Z. Xu§ and P. Casali§. 2015. B cell Rab7 mediates induction of AID expression and class-switching in T-dependent and T-independent antibody responses. J. Immunol.194: 3065-3078 (§co-senior authors).

Assistant Professor

Education

Ph.D., University of Southern California, 2002

Contact

Room 5.016V
Tel: (210) 567-3964
Fax: (210) 567-6612
Email: xuz3@uthscsa.edu

Graduate Students

Zheng Lou, Ph.D. Postdoctoral Fellow

Carlos Ecuador Rivera, M.S. Graduate Student, The UTHSCSA IBMS Program

Rui Wang M.D. student, Xiangya School of Medicine, China