Sankar Ghosh

Columbia University, New York, New York, United States

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Publications (109)1476.04 Total impact

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    ABSTRACT: Physiological bone remodeling requires that bone formation by osteoblasts be tightly coupled to bone resorption by osteoclasts. However, relatively little is understood about how this coupling is regulated. Here, we demonstrate that modulation of NF-κB signaling in osteoclasts via a novel activity of charged multivesicular body protein 5 (CHMP5) is a key determinant of systemic rates of bone turnover. A conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption by osteoclasts coupled with exuberant bone formation by osteoblasts, resembling an early onset, polyostotic form of human Paget's disease of bone (PDB). These phenotypes are reversed by haploinsufficiency for Rank, as well as by antiresorptive treatments, including alendronate, zolendronate, and OPG-Fc. Accordingly, CHMP5-deficient osteoclasts display increased RANKL-induced NF-κB activation and osteoclast differentiation. Biochemical analysis demonstrated that CHMP5 cooperates with the PDB genetic risk factor valosin-containing protein (VCP/p97) to stabilize the inhibitor of NF-κBα (IκBα), down-regulating ubiquitination of IκBα via the deubiquitinating enzyme USP15. Thus, CHMP5 tunes NF-κB signaling downstream of RANK in osteoclasts to dampen osteoclast differentiation, osteoblast coupling and bone turnover rates, and disruption of CHMP5 activity results in a PDB-like skeletal disorder. © 2015 Greenblatt et al.
    Journal of Experimental Medicine 07/2015; DOI:10.1084/jem.20150407 · 13.91 Impact Factor
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    ABSTRACT: Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did not inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 07/2015; 420. DOI:10.1016/j.bbrc.2015.07.008 · 2.28 Impact Factor
  • Thomas S. Postler · Sankar Ghosh
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    ABSTRACT: A close connection between inflammation and cancer has now been firmly established. While tumor initiation is typically independent of inflammatory events, immune cells infiltrating the tumor microenvironment secrete inflammatory cytokines that enhance the aberrant growth of tumor cells and thus facilitate tumor progression. Therefore, inflammation and tumor growth are usually interpreted as closely related on a systemic level but as distinct, independently regulated processes at a molecular level. Recently, we reported that a sub-class of small GTPases, namely κB-Ras1 and κB-Ras2, regulate both inflammation and tumor growth, thereby providing a unique molecular bridge between the two biological processes. Here, we briefly summarize the known contact points between inflammation and cancer, including oral cancers, and put into context the identification of κB-Ras proteins as molecular link between two independent pathways important for tumor growth.
    Journal of Oral Biosciences 06/2015; 57(3). DOI:10.1016/j.job.2015.05.001
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    ABSTRACT: Psoriasis is an inflammatory skin disease in which activated immune cells and the proinflammatory cytokine TNF are well-known mediators of pathogenesis. The transcription factor NF-κB is a key regulator of TNF production and TNF-induced proinflammatory gene expression, and both the psoriatic transcriptome and genetic susceptibility further implicate NF-κB in psoriasis etiopathology. However, the role of NF-κB in psoriasis remains controversial. We analyzed the function of canonical NF-κB in the epidermis using CRE-mediated deletion of p65 and c-Rel in keratinocytes. In contrast to animals lacking p65 or c-Rel alone, mice lacking both subunits developed severe dermatitis after birth. Consistent with its partial histological similarity to human psoriasis, this condition could be prevented by anti-TNF treatment. Moreover, regulatory T cells in lesional skin played an important role in disease remission. Our results demonstrate that canonical NF-κB in keratinocytes is essential for the maintenance of skin immune homeostasis and is protective against spontaneous dermatitis. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 02/2015; 194(6). DOI:10.4049/jimmunol.1402608 · 5.36 Impact Factor
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    Matthew S Hayden · Sankar Ghosh
    Proceedings of the National Academy of Sciences 11/2014; 111(49). DOI:10.1073/pnas.1419689111 · 9.81 Impact Factor
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    ABSTRACT: The transformation of cells generally involves multiple genetic lesions that undermine control of both cell death and proliferation. We now report that κB-Ras proteins act as regulators of NF-κB and Ral pathways, which control inflammation/cell death and proliferation, respectively. Cells lacking κB-Ras therefore not only show increased NF-κB activity, which results in increased expression of inflammatory mediators, but also exhibit elevated Ral activity, which leads to enhanced anchorage-independent proliferation (AIP). κB-Ras deficiency consequently leads to significantly increased tumor growth that can be dampened by inhibiting either Ral or NF-κB pathways, revealing the unique tumor-suppressive potential of κB-Ras proteins. Remarkably, numerous human tumors show reduced levels of κB-Ras, and increasing the level of κB-Ras in these tumor cells impairs their ability to undergo AIP, thereby implicating κB-Ras proteins in human disease.
    Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.015 · 8.36 Impact Factor
  • Matthew S. Hayden · Sankar Ghosh
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    ABSTRACT: The NF-κB family of inducible transcription factors is activated in response to a variety of stimuli. Amongst the best-characterized inducers of NF-κB are members of the TNF family of cytokines. Research on NF-κB and TNF have been tightly intertwined for more than 25 years. Perhaps the most compelling examples of the interconnectedness of NF-κB and the TNF have come from analysis of knock-out mice that are unable to activate NF-κB. Such mice die embryonically, however, deletion of TNF or TNFR1 can rescue the lethality thereby illustrating the important role of NF-κB as the key regulator of transcriptional responses to TNF. The physiological connections between NF-κB and TNF cytokines are numerous and best explored in articles focusing on a single TNF family member. Instead, in this review, we explore general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the so-called canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively.
    Seminars in Immunology 06/2014; 26(3). DOI:10.1016/j.smim.2014.05.004 · 6.12 Impact Factor
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    ABSTRACT: A20 has been suggested to limit NF-κB activation by removing regulatory ubiquitin chains from ubiquitinated substrates. A20 is a ubiquitin-editing enzyme that removes K63-linked ubiquitin chains from adaptor proteins, such as RIP1, and then conjugates them to K48-linked polyubiquitin chains to trigger proteasomal degradation. To determine the role of the deubiquitinase function of A20 in downregulating NF-κB signaling, we have generated a knock-in mouse that lacks the deubiquitinase function of A20 (A20-OTU mice). These mice are normal and have no signs of inflammation, have normal proportions of B, T, dendritic, and myeloid cells, respond normally to LPS and TNF, and undergo normal NF-κB activation. Our results thus indicate that the deubiquitinase activity of A20 is dispensable for normal NF-κB signaling.
    EMBO Reports 05/2014; 15(7). DOI:10.15252/embr.201338305 · 7.86 Impact Factor
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    ABSTRACT: Fibroblast growth factor-inducible 14 (Fn14) is a highly inducible cytokine receptor that engages multiple intracellular signaling pathways, including nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK). Fn14 expression is regulated by several cytokines and growth factors, and Fn14 is transiently upregulated after injury. In contrast, in states of chronic inflammatory disease and in some solid tumors Fn14 is persistently upregulated. However, the post-translational regulation of Fn14 expression has not been directly investigated. Thus, we have examined Fn14 proteostasis in the presence and absence of the Fn14 ligand TNF-like weak inducer of apoptosis (TWEAK). Similar to other TNF receptor superfamily members, we found that TWEAK induces Fn14 internalization and degradation. Surprisingly, we also observed rapid, TWEAK-independent, constitutive Fn14 internalization and turnover. Fn14 levels are maintained in cell culture by ongoing synthesis and trafficking of the receptor leading to subsequent downregulation by lysosomal degradation. Unexpectedly, the extracellular domain of Fn14 is necessary and sufficient for constitutive turnover. Based on these findings, we propose a model in which constitutive downregulation of Fn14 facilitates dynamic regulation of Fn14 protein levels and prevents spontaneous or inappropriate receptor signaling.
    Journal of Biological Chemistry 03/2014; 289(19). DOI:10.1074/jbc.M114.563478 · 4.57 Impact Factor
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    Dev Bhatt · Sankar Ghosh
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    ABSTRACT: The NF-κB family of transcription factors plays a central role in the inducible expression of inflammatory genes during the immune response, and the proper regulation of these genes is a critical factor in the maintenance of immune homeostasis. The chromatin environment at stimulus-responsive NF-κB sites is a major determinant in transcription factor binding, and dynamic alteration of the chromatin state to facilitate transcription factor binding is a key regulatory mechanism. NF-κB is in turn able to influence the chromatin state through a variety of mechanisms, including the recruitment of chromatin modifying co-activator complexes such as p300, the competitive eviction of negative chromatin modifications, and the recruitment of components of the general transcriptional machinery. Frequently, the selective interaction with these co-activators is dependent on specific post-translational modification of NF-κB subunits. Finally, the mechanisms of inducible NF-κB activity in different immune cell types seem to be largely conserved. The diversity of cell-specific NF-κB-mediated transcriptional programs is established at the chromatin level during cell differentiation by lineage-defining transcription factors. These factors generate and maintain a cell-specific chromatin landscape that is accessible to NF-κB, thus restricting the inducible transcriptional response to a cell-appropriate output.
    Frontiers in Immunology 02/2014; 5:71. DOI:10.3389/fimmu.2014.00071
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    ABSTRACT: Previous studies have implicated NF-κB signaling in both cutaneous development and oncogenesis. However, these studies have been limited in part by the lethality that results from extreme over- or under-expression of NF-κB in available mouse models. Even cre-driven tissue specific expression of transgenes, or targeted deletion of NF-κB can cause cell death. Therefore, the present study was undertaken to evaluate a novel mouse model of enhanced NF-κB activity in the skin. A knock-in homologous recombination technique was utilized to develop a mouse model (referred to as PD mice) with increased NF-κB activity. The data show that increased NF-κB activity leads to hyperproliferation and dysplasia of the mouse epidermis. Chemical carcinogenesis in the context of enhanced NF-κB activity promotes the development of keratoacanthomata. Our findings support an important role for NF-κB in keratinocyte dysplasia. We have found that enhanced NF-κB activity renders keratinocytes susceptible to hyperproliferation and keratoacanthoma (KA) development but is not sufficient for transformation and SCC development. We therefore propose that NF-κB activation in the absence of additional oncogenic events can promote TNF-dependent, actinic keratosis-like dysplasia and TNF-independent, KAs upon chemical carcinogensis. These studies suggest that resolution of KA cannot occur when NF-κB activation is constitutively enforced.
    PLoS ONE 08/2013; 8(8):e71887. DOI:10.1371/journal.pone.0071887 · 3.23 Impact Factor
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    ABSTRACT: Strong NF-κB activation requires ligation of both the CD28 coreceptor and TCR. Phosphoinositide-dependent kinase 1 (PDK1) acts as a scaffold by binding both protein kinase Cθ (PKCθ) and CARMA1, and is therefore essential for signaling to NF-κB. In this article, we demonstrate the importance of PDK1 Thr(513) phosphorylation in regulating the intermolecular organization of PDK1 homodimers. Thr(513) is directly involved in heterotypic PDK1 homodimer formation, in which binding is mediated through the pleckstrin homology (PH) and kinase domains. Upon activation, phosphorylated Thr(513) instead mediates homotypic intermolecular binding through the PH domains. Consequently, cell-permeable peptides with a Thr(513) to Ile derivative (protein transduction domain [PTD]-PDK1-Thr(513)-Ile) bound the kinase domain, whereas a Thr(513)-to-Asp peptide (PTD-PDK1-Thr(513)-Asp) bound the PH domain. PTD-PDK1-Thr(513)-Ile blocked binding between PDK1 and PKCθ, phosphorylation of PKCθ Thr(538), and activation of both NF-κB and AKT. In contrast, PTD-PDK1- Thr(513)-Asp selectively inhibited binding between PDK1 and CARMA1, and blocked TCR/CD28-induced NF-κB activation. Therefore, Thr(513) phosphorylation regulates a critical intermolecular switch governing PDK1 homodimer structure and the capacity to interact with downstream signaling pathway components. Given the pleiotropic functions of PDK1, these data may open the door to the development of immunosuppressive therapies that selectively target the PDK1 to NF-κB pathway in T cell activation.
    The Journal of Immunology 03/2013; 190(9). DOI:10.4049/jimmunol.1202923 · 5.36 Impact Factor
  • Hyunju Oh · Sankar Ghosh
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    ABSTRACT: The nuclear factor-κB (NF-κB) family of transcription factors plays important roles in various biological processes including apoptosis, stress response, immunity, and inflammation. NF-κB signaling is involved in both immune cell development and function, and it is critical in modulation of the immune response through the transcriptional regulation of cytokine and chemokine expression. An area of great interest in T-cell-mediated adaptive immunity is the ability of naive CD4(+) T cells generated in the thymus to differentiate into various subsets including T-helper 1 (Th1), Th2, Th17, Th9, follicular helper T (Tfh), Th22, and regulatory T (Treg) cells, upon encountering different pathogens and microenvironments. In this review, we discuss the role of NF-κB pathway in the development and functional divergence of the different helper T-cell subsets as well as in regulatory T cells.
    Immunological Reviews 03/2013; 252(1):41-51. DOI:10.1111/imr.12033 · 12.91 Impact Factor
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    ABSTRACT: Phosphoinositide-dependent kinase 1 (PDK1) plays an important role in integrating the T cell antigen receptor (TCR) and CD28 signals to achieve efficient NF-κB activation. PDK1 is also an important regulator of T cell development, mediating pre-TCR induced proliferation signals. However, the role of PDK1 in B cell antigen receptor (BCR) signaling and B cell development remains largely unknown. In this study we provide genetic evidence supporting the role of PDK1 in B cell survival. We found PDK1 is required for BCR mediated survival in resting B cells, likely through regulation of Foxo activation. PDK1-dependent signaling to NF-κB is not crucial to resting B cell viability. However, PDK1 is necessary for triggering NF-κB during B cell activation and is required for activated B cell survival. Together these studies demonstrate that PDK1 is essential for BCR-induced signal transduction to Foxo and NF-κB and is indispensable for both resting and activated B cell survival.
    PLoS ONE 02/2013; 8(2):e55378. DOI:10.1371/journal.pone.0055378 · 3.23 Impact Factor
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    ABSTRACT: Toll-like receptor 11 (TLR11) recognizes T. gondii profilin (TgPRF) and is required for interleukin-12 production and induction of immune responses that limit cyst burden in Toxoplasma gondii-infected mice. However, TLR11 only modestly affects survival of T. gondii-challenged mice. We report that TLR12, a previously uncharacterized TLR, also recognized TgPRF. TLR12 was sufficient for recognition of TgPRF by plasmacytoid dendritic cells (pDCs), whereas TLR11 and TLR12 were both required in macrophages and conventional DCs. In contrast to TLR11, TLR12-deficient mice succumb rapidly to T. gondii infection. TLR12-dependent induction of IL-12 and IFN-α in pDCs led to production of IFN-γ by NK cells. Consistent with this observation, the partial resistance of Tlr11(-/-) mice is lost upon pDC or NK cell depletion. Thus, TLR12 is critical for the innate immune response to T. gondii, and this TLR may promote host resistance by triggering pDC and NK cell function.
    Immunity 12/2012; 38(1). DOI:10.1016/j.immuni.2012.09.016 · 19.75 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) are key molecular sensors used by the mammalian innate immune system to detect microorganisms. Although TLR functions in colonic immune homeostasis and tolerance to commensal bacteria have been intensively researched, the precise roles of different TLRs in response to pathogen infection in the gut remain elusive. Peyer patches are the major entrance of Salmonella infection and antigen transportation in intestine. Here, we report that, in contrast to TLR5 as a carrier of Salmonella, TLR11 works as a blocker of Salmonella to prevent highly invasive Salmonella from penetrating into the murine Peyer patches and spreading systemically. TLR11 plays an important role in mediating TNF-alpha induction and systemic inflammation in response to Salmonella infection. Remarkably, mice lacking TLR11 are induced apparent hemorrhage at Peyer patches by highly invasive Salmonella, a phenotype resembling human Salmonella infection. Therefore, our results indicate a potentially important role for TLR11 in preventing murine intestinal infection and modulating antigen transportation in the gut and imply an important role for various TLRs in cooperation to tightly control of pathogens penetrating into Peyer patches. TLR11 knockout mouse can serve as a good animal model to study Salmonella infection.
    Journal of Biological Chemistry 11/2012; DOI:10.1074/jbc.M112.411009 · 4.57 Impact Factor
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    ABSTRACT: Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11(-/-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.
    Cell 10/2012; 151(3):590-602. DOI:10.1016/j.cell.2012.08.042 · 33.12 Impact Factor
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    Sankar Ghosh · Matthew S Hayden
    Immunological Reviews 03/2012; 246(1):5-13. DOI:10.1111/j.1600-065X.2012.01111.x · 12.91 Impact Factor
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    Matthew S Hayden · Sankar Ghosh
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    ABSTRACT: The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.
    Genes & development 02/2012; 26(3):203-34. DOI:10.1101/gad.183434.111 · 12.64 Impact Factor
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    Ulf Klein · Sankar Ghosh
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    ABSTRACT: Constitutive activation of NF-κB signaling can promote oncogenesis, providing a rationale for anticancer strategies that inhibit NF-κB signaling. Two recent publications in Genes & Development provide evidence that, in contexts where prosurvival signals derive from other oncogenes, NF-κB activity instead enhances sensitivity to cytotoxic chemotherapy, thereby exerting a tumor-suppressor function.
    Cancer cell 11/2011; 20(5):556-8. DOI:10.1016/j.ccr.2011.10.026 · 23.89 Impact Factor

Publication Stats

25k Citations
1,476.04 Total Impact Points

Institutions

  • 2009–2015
    • Columbia University
      • • College of Physicians and Surgeons
      • • Department of Microbiology and Immunology
      New York, New York, United States
  • 2013
    • Gwangju Institute of Science and Technology
      • Department of Life Sciences
      Gwangju, Gwangju, South Korea
  • 2012
    • CUNY Graduate Center
      New York, New York, United States
  • 1995–2009
    • Yale University
      • • Department of Molecular Biophysics and Biochemistry
      • • Department of Immunobiology
      • • Department of Cell Biology
      New Haven, Connecticut, United States
    • Memorial Sloan-Kettering Cancer Center
      • Division of Molecular Biology
      New York, New York, United States
  • 2004–2008
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2007
    • Universität Ulm
      • Institute of Physiological Chemistry
      Ulm, Baden-Württemberg, Germany
  • 2006
    • Ludwig Institute for Cancer Research
      لا هویا, California, United States
  • 1996–2005
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States