Sankar Ghosh, Ph.D.
Research in our laboratory is focused on understanding how engagement of receptors of both the innate and adaptive immune system lead to the activation of appropriate cellular responses through the inducible transcription factor, NF-kB. NF-kB plays a critical role in regulating the expression of a large number of genes involved in immune, inflammatory and apoptotic processes. NF-kB can be activated by different stimuli such as microbial products, proinflammatory cytokines, T and B cell mitogens and physical and chemical stresses. NF-kB in turn regulates the inducible expression of many cytokines, chemokines, adhesion molecules, acute phase proteins and anti-microbial peptides. Therefore NF-kB plays a central, evolutionarily conserved role in coordinating immune and inflammatory responses. In unstimulated cells, NF-kB is retained in the cytoplasm through its interaction with the inhibitory IkB proteins. Stimulation of cells with different inducers leads to the phosphorylation and subsequent degradation of the IkB proteins. Upon degradation of IkB, the free NF-kB enters the nucleus, however translocation of NF-kB to the nucleus is, in itself, not sufficient to drive transcription of target genes. Instead, specific phosphorylation of one of the NF-kB subunits, p65/RelA, is required for both efficient DNA-binding and transcriptional activity of the nuclear NF-kB.
We wish to understand the mechanisms that operate in the signal transduction pathways that lead to NF-kB activation, as well as the regulatory mechanisms that control the activity of NF-kB in the nucleus. Specific projects that are underway at present are listed below.
1. Understanding the mechanism by which signals from Toll/IL-1 receptors, TNF receptor and the T-cell receptor lead to NF-kB activation.
2. Characterizing the mechanism by which the transcriptional activity of nuclear NF-kB is regulated.
3. Exploring the dysregulation of NF-kB activity in diseases such as arthritis and cancer.
4. Understanding the biology of novel Toll-like receptors in response to infection.
Review Articles & Book Chapters
- Dainichi, T., Hayden, M.S., Park, S.-G., Oh, H., Seeley, J.J., Grinberg-Bleyer, Y., Beck, K.M., Miyachi, Y., Kabashima, K., Hashimoto, T. and Ghosh, S. (2016) PDK1 is a regulator of epidermal differentiation that activates and organizes asymmetric cell division. Cell Rep. 15: 1-9.
- Castellanos-Rubio, A., Fernandez-Jimenez, N., Kratchmarov, R., Luo, X., Bhagat, G., Green, P.H.R., Schneider, R., Kiledjian, M., Bilbao, J.R. and Ghosh, S. (2016) A long noncoding RNA associated with susceptibility to celiac disease. Science 352: 91-95.
- Greenblatt, M.B., Park, K.H., Oh, H., Kim, J.M., Shin, D.Y., Lee, J.M., Lee, J.W., Singh, A., Lee, K.Y., Hu, D., Xiao, C., Charles, J.F., Penninger, J.M., Lotinun, S., Baron, R., Ghosh, S. and Shim, J.H. (2015) CHMP5 controls bone turnover rates by dampening NF-kappaB activity in osteoclasts. J. Exp. Med. 212: 1283-1301.
- Grinberg-Bleyer, Y., Dainichi, T., Oh, H., Heise, N., Klein, U., Schmid, R.M., Hayden, M.S. and Ghosh, S. (2015) Cutting edge: NF-kappaB p65 and c-Rel control epidermal development and immune homeostasis in the skin. J. Immunol. 194: 2472-2476.
- Oeckinghaus, A., Postler, T.S., Rao, P., Schmitt, H., Schmitt, V., Grinberg-Bleyer, Y., Kuhn, L.I., Gruber, C.W., Lienhard, G.E. and Ghosh S. (2014) kB-Ras proteins regulate both NF-kB-dependent inflammation and Ral-dependent proliferation. Cell Rep. 8: 1793-1807.
- Koblansky, A.A., Jankovic, D., Oh, H., Hieny, S., Sungnak, W., Mathur, R., Hayden, M.S., Akira, S., Sher, A. and Ghosh, S. (2013) Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity 38: 119-130.
- Mathur, R., Oh, H., Zhang, D., Park, S.-G., Seo, J., Koblansky, A., Hayden, M.S. and Ghosh, S. (2012) A mouse model of Salmonella Typhi infection. Cell 151: 590-602.
- West, A.P., Brodsky, I.E., Rahner, C., Woo, D.K., Erdjument-Bromage, H., Tempst, P., Walsh, M.C., Choi, Y., Shadel, G.S. and Ghosh, S. (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472: 476-480.
- Park, S.G., Mathur, R., Long, M., Hosh, N., Hao, L., Hayden, M.S. and Ghosh, S. (2010) T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells. Immunity 33: 791-803.
- Rao, P., Hayden, M.S., Long, M., Scott, M.L., Philip West, A., Zhang, D., Oeckinghaus, A., Lynch, C., Hoffmann, A., Baltimore, D. and Ghosh, S. (2010) IkBβ acts to inhibit and activate gene expression during the inflammatory response. Nature 466: 1115-1119.
- Dong, J., Jimi E., Zeiss C., Hayden M.S. and Ghosh, S. (2010) Constitutively active NF-kB triggers systemic TNFα-dependent inflammation and localized TNFα-independent inflammatory disease. Genes & Development 24: 1709-1717.
- Long, M., Park, S.-G., Strickland, I., Hayden, M.S. and Ghosh, S. (2009) Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 18: 921-931.
- Park, S.-G., Schulze-Luehrman, J., Hayden, M.S., Hashimoto, N., Ogawa, W., Kasuga, M. and Ghosh, S. (2009) PDK1 integrates TCR and CD28 signaling to NF-kB. Nature Immunology 10: 158-166.
- Jimi, E., Voll, R. E., Strickland, I., Long, M. and Ghosh, S. (2008) Differential role of NF-kB in selection and survival of CD4 and CD8 thymocytes. Immunity 29: 523-537.
- Dong, J., Jimi, E., Zhong, H., Hayden, M.S. and Ghosh S. (2008) Epigenetic regulation of NF-kB dependent gene expression. Genes & Development 22: 1159-1173.
- Shim, J.-H., Xiao, C., Paschal, A., Bailey, S.T., Rao, P., Hayden, M.S., Lee, K.Y., Bussey, C., Steckel, M., Tanaka, N., Akira, S., Yamada, G., Matsumoto, S. and Ghosh, S. (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes & Development 19: 2668-2681.
- Yarovinsky, F., Zhang, D., Andersen, J.F., Bannenberg, G.L., Serhan, C.N., Hayden, M.S., Hieny, S., Sutterwala, F., Flavell, R. A., Ghosh, S. and Sher, A. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308: 1626-1629.
- Lee, K.-Y., D'Acquisto, F., Hayden, M.S., Shim, J.-H. and Ghosh, S. (2005) Protein kinase PDK1 nucleates T-cell receptor-induced signaling complex for NF-kB activation. Science 308: 114-118.
- Jimi, E., Aoki, K., Saito, H., D'Acquisto, F., May, M.J., Ichiro Nakamura, I., Sudo, T., Ohya, K. and Ghosh, S. (2004) Selective inhibition of NF-kB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nature Medicine 10: 617-624.
- Zhang, D., Zhang, G., Hayden, M.S., Greenblatt, M.S., Bussey, C., Flavell, R.A. and Ghosh, S. (2004) A novel Toll-like receptor that prevents infection of kidneys by uropathogenic bacteria. Science 303: 1522-1526.
- Xiao, C., Shim, J-H., Kluppel, M., Zhang, S-M., Dong, C., Flavell, R.A., Fu, X-Y., Wrana, J. L., Hogan, B.L.M. and Ghosh, S. (2003) Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes & Development 17: 2933-2949.
- Zhong, H., May, M.J., Jimi, E. and Ghosh, S. (2002) Phosphorylation of nuclear NF-kB governs its association with either HDAC-1 or CBP/p300: a mechanism for regulating the transcriptional activity of NF-kB. Molecular Cell 9: 625-636.
- May, M.J., D'Acquisto, F., Madge, L.A., Gloeckner, J., Pober, J.S. and Ghosh, S. (2000) Selective inhibition of NFk-B activation by a peptide that blocks the interaction of NEMO with the IkB kinase complex. Science 289: 1550-1554.
- Voll, R.E., Jimi, E., Phillips, R.J., Barber, D.F., Rincon. M., Hayday, A.C., Flavell, R.A. and Ghosh, S. (2000) NFk-B Activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13: 677-689.
- Li, B., Yu, H., Zheng, W., Voll, R., Na, S., Roberts, A., Williams, D.A., Davis, R.J., Ghosh, S. and Flavell, R.A. (2000) Role of the guanosine triposphatase Rac2 in T helper 1 cell differentiation. Science 288: 2219-2222.
- Fenwick, C., Na, S-Y., Voll, R.E., Zhong, H., Im, S-Y., Lee, J.W. and Ghosh, S. (2000) A sub-class of Ras proteins that regulate the degradation of IkappaB. Science 287: 869-873.
- Kopp, E., Medzhitov, R., Carothers, J., Xiao, C., Douglas, I., Janeway, C.A. and Ghosh, S. (1999) ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes & Development 13: 2059-2071.
- Medzhitov, R., Kopp, E.B., Ghosh, S. and Janeway, C.A. (1998) MyD88 is a common intermediate in the IL-1 and Toll signal transduction pathways. Molecular Cell 2: 253-258.
- Zhong, H., Voll, R.E. and Ghosh, S. (1998) Phosphorylation of NF-kB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the co-activator CBP/p300. Molecular Cell 1: 661-671.
- Zhong, H., SuYang, H., Erdjument-Bromage, H., Tempst, P. and Ghosh, S. (1997) The transcriptional activity of NF-kB is regulated by IkB-associated PKAc subunit through a cyclic AMP independent mechanism. Cell 89: 413-424.
- Beg, A.A., Sha, W.C., Bronson, R.T., Ghosh, S. and Baltimore, D. (1995) Embyronic lethality and liver degeneration in mice lacking the RelA component of NF-kB. Nature 376: 167-170.
- Ghosh, G., Van Duyne, G., Ghosh, S. and Sigler, P.B. (1995) Structure of NF-kappa B p50 homodimer bound to a kappa B site. Nature 373: 303-310.
- Thompson, J.E., Phillips, R.J., Erdjument-Bromage, H., Tempst, P. and Ghosh, S. (1995) IkB-ß regulates the persistent response in a biphasic activation of NFk-B. Cell 80: 573-582.
- Kopp, E. and Ghosh, S. (1994) Inhibition of NF-kB by sodium salicylate and aspirin. Science 265: 956-959.
- Davis, N.*, Ghosh, S.*, Simmons, D.L., Tempst, P., Liou, H.C., Baltimore, D. and Bose, H.R. Jr. (1991) Rel-associated pp40 (IkappaB alpha): an inhibitor of the rel family of transcription factors. Science 253: 1268-1271. (*equal contribution)
- Nolan, G.P., Ghosh, S., Liou, H.C., Tempst, P. and Baltimore, D. (1991) DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell 64: 961-969.
- Ghosh, S., Gifford, A.M., Riviere, L.R., Tempst, P., Nolan, G.P. and Baltimore, D. (1990) Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell 62: 1019-1029.
- Ghosh, S. and Baltimore, D. (1990) Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 344: 678-682.
- Grinberg-Bleyer, Y. and Ghosh, S. (2016) A novel link between inflammation and cancer. Cancer Cell 12: 829-830.
- Lepelley, A. and Ghosh, S. (2016) Clean up after yourself. Mol. Cell 61: 644-645.
- Hayden, M.S. and Ghosh, S. (2014) Innate sense of purpose for IKKβ. Proc. Natl. Acad. Sci. U.S.A. 111: 17348-17349.
- Hayden, M.S. and Ghosh, S. (2012) NF-kB, the first quarter-century: remarkable progress and outstanding questions. Genes & Development 26: 203-234.
- Klein, U. and Ghosh, S. (2011) The two faces of NF-kB signaling in cancer development and therapy. Cancer Cell 20: 556-558.
- Oeckinghaus, A., Hayden, M.S. and Ghosh, S. (2011) Crosstalk in NF-kB signaling pathways. Nature Immunology 12: 695-708.
- West, A.P., Shadel, G.S. and Ghosh, S. (2011) Mitochondria in innate immune responses. Nature Reviews Immunology 11: 389-402. Featured article.
- Baker, R.G., Hayden, M.S. and Ghosh, S. (2011) NF-kappaB, inflammation, and metabolic disease. Cell Metabolism 13: 11-22.
- Hayden, M.S. and Ghosh, S. (2008) New regulators of NF-kappaB in inflammation. Nature Reviews Immunology 8: 837-848.
- Hayden, M.S. and Ghosh, S. (2008) Shared principles in NF-kappaB signaling. Cell 132: 344-362.
- Hayden, M.S., West, A.P. and Ghosh, S. (2006) SnapShot: NF-kappaB signaling pathways. Cell 127: 1286-1287.
- Schulze-Luehrmann, J. and Ghosh, S. (2006) Antigen-receptor signaling to nuclear factor kappa B. Immunity 25: 701-715.
- West, A.P., Koblansky, A.A. and Ghosh, S. (2006) Recognition and signaling by toll-like receptors. Annual Review of Cell and Developmental Biology 22: 409-437.
- Hayden, M.S. and Ghosh, S. (2004) Signaling to NF-kappaB. Genes & Development 18: 2195-2224.
- Ghosh, S. and Karin, M. (2002) Missing pieces in the NF-kappaB puzzle. Cell 109: S81-S96.
- Ghosh, S., May, M.J. and Kopp, E.B. (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16: 225-260.
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