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.
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.
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.
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
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.
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
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.
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
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
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
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
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).