Williams Endowed Chair and Professor of Immunology and PathogenesisLab Homepage: http://mcb.berkeley.edu/labs/winoto/
Our lab is interested in the molecular mechanisms of cell death (apoptosis and programmed necrosis), T cell development and innate immunity. We are using a combination of biochemical, molecular biological and mouse transgenic/gene targeting approaches in our studies.
Fas and a subset of related tumor necrosis factor (TNF) receptor family members contain a death domain in their cytoplasmic tails. Stimulation by the corresponding TNF ligand family members leads to recruitment of an adapter protein called FADD. FADD in turn recruits caspase 8, activation of which can lead to cell death. FADD is a universal adapter for all receptor-mediated death but surprisingly, FADD and caspase-8 are also negative regulators of an alternative form of cell death called necroptosis (programmed necrosis). Loss of FADD leads to resistance to apoptosis but FADD-deficient cells undergo necroptosis instead. Current projects are aimed to understand the physiological role of necroptosis in the immune system.
The orphan steroid nuclear receptor Nur77 and its family member are genes that can be induced by T-cell receptor (TCR) stimulation. Nur77 is unique in that its transcription levels reflect the strength of TCR signaling. During T cell development, a strong TCR signal usually leads to apoptosis (negative selection) while a moderate TCR signalling leads to production of regulatory T cells. T cell specific loss of the Nur77 family leads to massive inflammation in mice due to the loss of Treg population and reduced negative selection. Nur77 induces transcription of several apoptotic molecules but Nur77 can also initiate apoptosis by translocating to mitochondria and converting the anti-apoptotic Bcl-2 protein into a pro-apoptotic molecule. Current projects are aimed to understand this novel mechanism of cell death and how Nur77 transcription is regulated by TCR signalling.
PTEN is a lipid phosphatase that negatively regulates the PI3 kinase-AKT pathway. Mutation in this PTEN tumor suppressor gene is frequently detected in human cancer. T-cell specific PTEN-deficient mice succumb to mature T cell lymphomas in spleen and lymph nodes by 16 weeks of age. However, development of lymphoma is dependent on changes first detected in immature thymoyctes at 8-9 weeks of age. Changes include activation of the AKT pathway and c-myc translocation. Transient elimination of immature thymocytes in adult mice led to a significant rescue of these mice from lymphoma and lethality. We are using this model to understand the molecular steps of lymphomagenesis.
Commensal Microbiota are Required for Systemic Inflammation Triggered by Necrotic Dendritic Cells [Young, J. A., He, T.H., Reizis, B. and Winoto, A. (2013) Cell Reports, 3, 1932-1944.
Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production [Young*, J. A., Sermwittayawong*, D., Kim, H., Nandu, S., An, N.S., Erdjument-Bromage, H., Tempst, P., Coscoy, L. and Winoto, A. (2011) J. Biol. Chem. 286, 6521-6531. *co-authorship]
FADD is a negative regulator of T cell receptor-mediated necroptosis [Osborn, S. L., Diehl, G., Hans, S-J., Xue, L., Kurd, N., Hsieh, K, Cado, D., Robey, E.A. and Winoto, A. (2010) Proc. Natl. Acad. Sci. USA. e107, 13034-13039]
Protein Kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis [Thompson, J., Burger, M., Whang, H. and Winoto, A. (2010) Eur. J. Immunol. 40, 2041-2049]
FoxM1, a Forkhead transcription factor is a master cell cycle regulator for mature but not immature mouse T cells [Xue, L, Chiang, L., He, B., Zhao, Y-Y, and Winoto, A. (2010) PLOS One, 5 (2):e9229]
Coupling of the cell cycle and apoptosis machineries in developing T cells [Xue, L., Sun, Y., Chiang, L., He, B., Kang, C. Nolla, H. and Winoto, A. (2010) J. Biol.Chem. 285, 7556-7565]
Normal Development is an Integral Part of Tumorigenesis in T-cell specific PTEN-deficient Mice [Xue, L., Nolla, H., Suzuki, A., Mak, T.W. and Winoto, A (2008) Proc. Natl. Acad. Sci. USA 105, 2022-2027]
Last Updated 2013-07-01