Weiguo Zhang

Overview:


Activation via the T-cell antigen receptor (TCR) triggers a cascade of intracellular biochemical events eventually leading to T-cell proliferation and effector functions. One of the earliest events is the activation of the Src family tyrosine kinases Fyn and Lck. The activated Src family kinases phosphorylate the CD3 subunits and TCRζ chains. ZAP-70 tyrosine kinase is recruited to the antigen receptors via the binding to CD3 and TCRζ. ZAP-70 is then tyrosine phosphorylated by these Src family kinases and thus activated. These activated tyrosine kinases further phosphorylate a number of intracellular proteins, such as PLC-γ1, Vav, Cbl, SLP-76, and LAT, and activate downstream signaling pathways including the Ras-MAPK pathway and Ca2+flux. Activation of these two pathways is required for AP-1 and NFAT-mediated transcription, IL-2 production, and T-cell proliferation.

Our primary interest of the laboratory is to understand the role of membrane-associated adaptor proteins in lymphocyte activation, development, and immune response. One of these proteins is LAT (Linker for Activation of T-cells). LAT is tyrosine phosphorylated upon T-cell activation and associates with several signaling molecules including Grb2, Gads, and PLC-γ1. LAT-deficient T-cells are defective in the Ras-MAPK activation and Ca2+ flux after the TCR engagement. LAT knockout mice have an early block in thymocyte development. Interestingly, mice with a mutation in LAT develop a severe autoimmune disease. We are investigating how LAT interacts with other signaling proteins and how LAT regulates T cell activation and immune responses.

In addition to LAT, we are working on two LAT-like molecules, LAB and LAX. We have generated mice deficient in these proteins and are analyzing the phenotypes of these mice to determine the role of these proteins in lymphocyte signaling and immune responses.

We are also interested in FcεRI-mediated signaling. We are working on the role of LAT, LAB, and RasGRP1 in FcεRI-mediated signaling, mast cell function, and allergic responses.

Our long-term goal is to understand the details of immunoreceptor-mediated signaling pathways. Understanding these signaling pathways may identify therapeutic targets that could facilitate the development of drugs that suppress, modify, or augment immune responses in autoimmunity, transplantation, allergy, and cancer.

Positions:

Associate Professor of Immunology

Immunology
School of Medicine

Director of Undergraduate Studies

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1994

Yeshiva University New York

Postdoctoral Fellow, Microbiology And Immunology

Yeshiva University New York

Postdoctoral Fellow, Cell Biology And Metabolism Branch

National Institutes of Health

Grants:

LAT in thymic selection of MHC-restricted T cells

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Phospholipase D proteins in immunoreceptor-mediated signaling

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Analysis of adaptor protein (LAT) in TCR signaling

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Adaptor molecules in lymphocyte signaling

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Basic Immunology Training Program

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Publications:

Extended ORF8 Gene Region Is Valuable in the Epidemiological Investigation of Severe Acute Respiratory Syndrome-Similar Coronavirus.

Severe acute respiratory syndrome coronavirus (SARS-CoV) was discovered as a novel pathogen in the 2002-2003 SARS epidemic. The emergence and disappearance of this pathogen have brought questions regarding its source and evolution. Within the genome sequences of 281 SARS-CoVs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and SARS-related CoVs (SARSr-CoVs), a ~430 bp genomic region (from 27 701 bp to 28 131 bp in AY390556.1) with regular variations was investigated. This ~430 bp region overlaps with the ORF8 gene and is prone to deletions and nucleotide substitutions. Its complexity suggested the need for a new genotyping method for coronaviruses related to SARS-similar coronaviruses (SARS-CoV, SARSr-CoV, and SARS-CoV-2). Bat SARSr-CoV presented 3 genotypes, of which type 0 is only seen in bat SARSr-CoV, type I is present in SARS in the early phase, and type II is found in all SARS-CoV-2. This genotyping also shows potential usage in distinguishing the SARS-similar coronaviruses from different hosts and geographic areas. This genomic region has important implications for predicting the epidemic trend and studying the evolution of coronavirus.
Authors
Chen, S; Zheng, X; Zhu, J; Ding, R; Jin, Y; Zhang, W; Yang, H; Zheng, Y; Li, X; Duan, G
MLA Citation
Chen, Shuaiyin, et al. “Extended ORF8 Gene Region Is Valuable in the Epidemiological Investigation of Severe Acute Respiratory Syndrome-Similar Coronavirus.The Journal of Infectious Diseases, vol. 222, no. 2, June 2020, pp. 223–33. Epmc, doi:10.1093/infdis/jiaa278.
URI
https://scholars.duke.edu/individual/pub1441138
PMID
32433742
Source
epmc
Published In
The Journal of Infectious Diseases
Volume
222
Published Date
Start Page
223
End Page
233
DOI
10.1093/infdis/jiaa278

MicroRNA-628-5p Facilitates Enterovirus 71 Infection by Suppressing TRAF3 Signaling.

Authors
Li, D; Chen, S; Zhang, W; Zhang, C; Sun, T; Du, Y; Ding, R; Gao, Y; Jin, Y; Duan, G
MLA Citation
Li, Dong, et al. “MicroRNA-628-5p Facilitates Enterovirus 71 Infection by Suppressing TRAF3 Signaling.Cellular & Molecular Immunology, May 2020. Epmc, doi:10.1038/s41423-020-0453-4.
URI
https://scholars.duke.edu/individual/pub1441287
PMID
32398803
Source
epmc
Published In
Cellular & Molecular Immunology
Published Date
DOI
10.1038/s41423-020-0453-4

Virology, Epidemiology, Pathogenesis, and Control of COVID-19.

The outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China has been brought to global attention and declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Scientific advancements since the pandemic of severe acute respiratory syndrome (SARS) in 2002~2003 and Middle East respiratory syndrome (MERS) in 2012 have accelerated our understanding of the epidemiology and pathogenesis of SARS-CoV-2 and the development of therapeutics to treat viral infection. As no specific therapeutics and vaccines are available for disease control, the epidemic of COVID-19 is posing a great threat for global public health. To provide a comprehensive summary to public health authorities and potential readers worldwide, we detail the present understanding of COVID-19 and introduce the current state of development of measures in this review.
Authors
Jin, Y; Yang, H; Ji, W; Wu, W; Chen, S; Zhang, W; Duan, G
MLA Citation
Jin, Yuefei, et al. “Virology, Epidemiology, Pathogenesis, and Control of COVID-19.Viruses, vol. 12, no. 4, Mar. 2020. Pubmed, doi:10.3390/v12040372.
URI
https://scholars.duke.edu/individual/pub1436675
PMID
32230900
Source
pubmed
Published In
Viruses
Volume
12
Published Date
DOI
10.3390/v12040372

Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination.

Self-non-self discrimination is central to T cell-mediated immunity. The kinetic proofreading model can explain T cell antigen receptor (TCR) ligand discrimination; however, the rate-limiting steps have not been identified. Here, we show that tyrosine phosphorylation of the T cell adapter protein LAT at position Y132 is a critical kinetic bottleneck for ligand discrimination. LAT phosphorylation at Y132, mediated by the kinase ZAP-70, leads to the recruitment and activation of phospholipase C-γ1 (PLC-γ1), an important effector molecule for T cell activation. The slow phosphorylation of Y132, relative to other phosphosites on LAT, is governed by a preceding glycine residue (G131) but can be accelerated by substituting this glycine with aspartate or glutamate. Acceleration of Y132 phosphorylation increases the speed and magnitude of PLC-γ1 activation and enhances T cell sensitivity to weaker stimuli, including weak agonists and self-peptides. These observations suggest that the slow phosphorylation of Y132 acts as a proofreading step to facilitate T cell ligand discrimination.
Authors
Lo, W-L; Shah, NH; Rubin, SA; Zhang, W; Horkova, V; Fallahee, IR; Stepanek, O; Zon, LI; Kuriyan, J; Weiss, A
MLA Citation
Lo, Wan-Lin, et al. “Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination.Nat Immunol, vol. 20, no. 11, Nov. 2019, pp. 1481–93. Pubmed, doi:10.1038/s41590-019-0502-2.
URI
https://scholars.duke.edu/individual/pub1416874
PMID
31611699
Source
pubmed
Published In
Nat Immunol
Volume
20
Published Date
Start Page
1481
End Page
1493
DOI
10.1038/s41590-019-0502-2

The role of LAT-PLCγ1 interaction in γδ T cell development and homeostasis.

LAT is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals to modulate T cell development, activation, and proliferation. Upon T cell activation, LAT is phosphorylated and associates with Grb2, Gads, and PLCγ1 through its four distal tyrosine residues. Mutation of one of these tyrosines, Y136, abolishes LAT binding to PLCγ1. This results in impaired TCR-mediated calcium mobilization and Erk activation. CD4 αβ T cells in LATY136F knock-in mice undergo uncontrolled expansion, resulting in a severe autoimmune syndrome. In this study, we investigated the importance of the LAT-PLCγ1 interaction in γδ T cells by crossing LATY136F mice with TCRβ(-/-) mice. Our data showed that the LATY136F mutation had no major effect on homeostasis of epithelial γδ T cells, which could be found in the skin and small intestine. Interestingly, a population of CD4(+) γδ T cells in the spleen and lymph nodes underwent continuous expansion and produced elevated amounts of IL-4, resulting in an autoimmune syndrome similar to that caused by αβ T cells in LATY136F mice. Development of these hyperproliferative γδ T cells was not dependent on MHC class II expression or CD4, and their proliferation could be suppressed, in part, by regulatory T cells. Our data indicated that a unique subset of CD4 γδ T cells can hyperproliferate in LATY136F mice and suggested that LAT-PLCγ1 signaling may function differently in various subsets of γδ T cells.
Authors
Sullivan, SA; Zhu, M; Bao, S; Lewis, CA; Ou-Yang, C-W; Zhang, W
MLA Citation
Sullivan, Sarah A., et al. “The role of LAT-PLCγ1 interaction in γδ T cell development and homeostasis.J Immunol, vol. 192, no. 6, Mar. 2014, pp. 2865–74. Pubmed, doi:10.4049/jimmunol.1302493.
URI
https://scholars.duke.edu/individual/pub1016073
PMID
24523509
Source
pubmed
Published In
J Immunol
Volume
192
Published Date
Start Page
2865
End Page
2874
DOI
10.4049/jimmunol.1302493