Sankar Ghosh, Ph.D.
Chairman and Silverstein and Hutt Family Professor of Microbiology & Immunology
Ph.D., Albert Einstein College of Medicine
Inflammation, immune responses and cancer
Groundbreaking discoveries over many decades have confirmed and elaborated on the close connection between the immune system and a host of diseases of major importance to public health, including cancer, sepsis, rheumatoid arthritis, asthma, diabetes and celiac disease. Recent technological breakthroughs have allowed us to gain unprecedented insight into the regulatory networks that govern immune responses. Medical interventions that manipulate the immune system to target cancer, so-called cancer immunotherapies, have seen spectacular results in the treatment of certain tumors. And this is just the beginning.
The Ghosh lab has a long-standing interest in understanding and elucidating the complexities of transcriptional regulation, with a particular focus on the innate and adaptive immune system. As pathological changes to the transcriptional programs of immune cells lie at the heart of many diseases, we aim to obtain a deep, mechanistic understanding of the pathways that establish, maintain and fine-tune the immunological transcriptome. Based on this knowledge, we hope to devise novel, innovative approaches to combat some of humanities most vexing afflictions.
Current projects in the Ghosh lab include:
We use biochemical, molecular and genetic techniques to study and understand the mechanisms that control the activation, activity and specificity of the transcription factor NF-κB, a central regulator of gene expression in all immune cells. We are aiming to elucidate how specific modulators of NF-κB influence gene expression by regulating particular NF-κB subunit combinations, that then allows expression of the appropriate genes in the appropriate cells at the appropriate time, a topic of particular relevance for autoimmune diseases such as sepsis. Furthermore, we are using cutting-edge genomic technologies, such as RNA-seq, ATAC-seq and ChIP-seq, to unravel the mechanisms by which inflammatory signals regulate the gene expression program of macrophages.
We are studying the importance of individual NF-κB subunits in the regulation of conventional, effector T cells and regulatory, suppressive T cells (Tregs). Our recent findings have established a central role of c-Rel in the suppression of anti-tumor activity; now, we are exploring approaches to specifically inhibit c-Rel as a novel strategy for enhancing current cancer immunotherapy regimens.
Long non-coding RNAs (lncRNAs) have recently emerged as important regulators of a plethora of physiological processes, including immune responses. We are using GWAS data to identify interesting lncRNA targets and study them in the context of inflammatory diseases, such as celiac disease and rheumatoid arthritis. We are also identifying and characterizing novel microRNA regulators of the inflammatory response.
Mitochondria serve as hubs that connect various signaling networks to inflammatory signaling. We are studying the role of ECSIT, a mitochondrial complex I chaperone, in the regulation of mitochondrial ROS production. We are also investigating a novel role of ECSIT in neurodegenerative diseases, including Parkinson's and Alzheimer's disease.
The microbiome has recently emerged as a crucial variable that affects diverse physiological processes. Dysregulation of the microbiome is associated with pathologies as diverse as metabolic disease, cancer, inflammatory bowel disease, and depression. We are interested in understanding how the function of certain Toll-like receptors (TLRs) is influenced by the microbiome in organs such as the gut and lungs, and how these TLRs in return shape the microbiome.
Postdoctoral positions available
Postdoctoral positions are available in the laboratory in the areas of cancer immunology and the regulation of inflammatory signaling. Expertise in flow cytometry and bioinformatic analysis is desirable. See the job postings in Science or Nature for details.
Seeley, J.J., Baker, R.G., Mohamed, G., Bruns, T., Hayden, M.S., Deshmukh, S.D., Freedberg, D.E and Ghosh, S. (2018) Induction of innate immune memory via microRNA targeting of chromatin remodelling factors. Nature 559: 114-119.
Grinberg-Bleyer, Y., Caron, R., Seeley, J.J., De Silva, N.S., Schindler, C.W., Hayden, M.S., Klein, U. and Ghosh, S. (2018) The alternative NF-κB pathway in regulatory T cell homeostasis and suppressive function. J. Immunol. 200: 2362-2371. (Cover article)
Carneiro, F.R.G., Lepelley, A., Seeley, J.J., Hayden, M.S. and Ghosh, S. (2018) An essential role for ECSIT in mitochondrial complex I assembly and mitophagy in macrophages. Cell Rep. 22:2654-2666.
Oh, H., Grinberg-Bleyer, Y., Liao, W., Maloney, D., Wang, P., Wu, Z., Wang, J., Bhatt, D.M., Heise, N., Schmid, R.M., Hayden, M.S., Klein, U., Rabadan, R., and Ghosh, S. (2017) An NF-κB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity 47: 450-465.
Grinberg-Bleyer, Y., Oh, H., Desrichard, A., Bhatt, D.M., Caron, R., Chan, T.A., Schmid, R.M., Klein, U., Hayden, M.S. and Ghosh, S. (2017) NF-κB c-Rel is crucial for the regulatory T cell immune checkpoint in cancer. Cell 170: 1096-1108.
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. Science265: 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. Cell64: 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.
Review Articles & Book Chapters
Postler, T.S. and Ghosh, S. (2017) Understanding the holobiont: How microbial metabolites affect human health and shape the immune system. Cell Metab. 26: 110-130.
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. Cell127: 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.