Publications by authors named "Laurie H Glimcher"

187 Publications

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Cell 2020 Dec 8;183(7):1826-1847.e31. Epub 2020 Dec 8.

St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY, USA. Electronic address:

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 γδ T lymphocytes, and of Mycobacterium-non reactive classic T1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 αβ T and non-classic CD4 αβ T1 lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 αβ T, and CD4 αβ T1 cells unable to compensate for this deficit.
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http://dx.doi.org/10.1016/j.cell.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770098PMC
December 2020

XBP-1 and the unfolded protein response (UPR).

Nat Immunol 2020 09;21(9):963-965

, Austin, GA, USA.

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http://dx.doi.org/10.1038/s41590-020-0708-3DOI Listing
September 2020

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

Science 2019 07;365(6450)

Weill Cornell Graduate School of Medical Sciences, Cornell University. New York, NY 10065, USA.

Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
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http://dx.doi.org/10.1126/science.aau6499DOI Listing
July 2019

The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc.

Nat Immunol 2019 07 13;20(7):865-878. Epub 2019 May 13.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.

Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.
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http://dx.doi.org/10.1038/s41590-019-0388-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588410PMC
July 2019

IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.

Nature 2018 10 10;562(7727):423-428. Epub 2018 Oct 10.

Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.
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http://dx.doi.org/10.1038/s41586-018-0597-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237282PMC
October 2018

Targeting skeletal endothelium to ameliorate bone loss.

Nat Med 2018 06 21;24(6):823-833. Epub 2018 May 21.

Department of Pathology and Laboratory Medicine, Cornell University, New York, NY, USA.

Recent studies have identified a specialized subset of CD31endomucin (CD31EMCN) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31EMCN endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31EMCN endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31EMCN endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3 mice. This coupling between osteoblasts and CD31EMCN endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.
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http://dx.doi.org/10.1038/s41591-018-0020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992080PMC
June 2018

T-bet Runs INTERFERence.

Immunity 2017 06;46(6):968-970

Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.

In this issue of Immunity, Iwata et al. (2017) report that the transcription factor T-bet acts as a selective repressor of the type I interferon (IFN) transcriptional program in response to IFN-γ signaling.
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http://dx.doi.org/10.1016/j.immuni.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685208PMC
June 2017

Post-translational control of T cell development by the ESCRT protein CHMP5.

Nat Immunol 2017 Jul 29;18(7):780-790. Epub 2017 May 29.

Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post-selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro-apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development.
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http://dx.doi.org/10.1038/ni.3764DOI Listing
July 2017

SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts.

Nat Commun 2017 02 20;8:14570. Epub 2017 Feb 20.

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Coordination between osteoblasts and osteoclasts is required for bone health and homeostasis. Here we show that mice deficient in SMURF2 have severe osteoporosis in vivo. This low bone mass phenotype is accompanied by a pronounced increase in osteoclast numbers, although Smurf2-deficient osteoclasts have no intrinsic alterations in activity. Smurf2-deficient osteoblasts display increased expression of RANKL, the central osteoclastogenic cytokine. Mechanistically, SMURF2 regulates RANKL expression by disrupting the interaction between SMAD3 and vitamin D receptor by altering SMAD3 ubiquitination. Selective deletion of Smurf2 in the osteoblast lineage recapitulates the phenotype of germline Smurf2-deficient mice, indicating that SMURF2 regulates osteoblast-dependent osteoclast activity rather than directly affecting the osteoclast. Our results reveal SMURF2 as an important regulator of the critical communication between osteoblasts and osteoclasts. Furthermore, the bone mass phenotype in Smurf2- and Smurf1-deficient mice is opposite, indicating that SMURF2 has a non-overlapping and, in some respects, opposite function to SMURF1.
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http://dx.doi.org/10.1038/ncomms14570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321737PMC
February 2017

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer.

Cell 2017 02;168(4):692-706

Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

Malignant cells utilize diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting the development of anti-tumor immune responses. Hostile microenvironmental conditions within tumor masses, such as nutrient deprivation, oxygen limitation, high metabolic demand, and oxidative stress, disturb the protein-folding capacity of the endoplasmic reticulum (ER), thereby provoking a cellular state of "ER stress." Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. Additionally, recent studies have uncovered that ER stress responses further impede the development of protective anti-cancer immunity by manipulating the function of myeloid cells in the tumor microenvironment. Here, we discuss the tumorigenic and immunoregulatory effects of ER stress in cancer, and we explore the concept of targeting ER stress responses to enhance the efficacy of standard chemotherapies and evolving cancer immunotherapies in the clinic.
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http://dx.doi.org/10.1016/j.cell.2016.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333759PMC
February 2017

Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites.

Proc Natl Acad Sci U S A 2016 10 10;113(43):E6572-E6581. Epub 2016 Oct 10.

Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021; Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454;

The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the T1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DBD dimer binds simultaneously to identical half-sites on two independent DNA. A fluorescence-based assay confirms that T-bet dimers are able to bring two independent DNA molecules into close juxtaposition. Furthermore, chromosome conformation capture assays confirm that T-bet functions in the direct formation of chromatin loops in vitro and in vivo. The data are consistent with a looping/synapsing model for transcriptional regulation by T-bet in which a single dimer of the transcription factor can recognize and coalesce distinct genetic elements, either a promoter plus a distant regulatory element, or promoters on two different genes.
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http://dx.doi.org/10.1073/pnas.1613914113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087062PMC
October 2016

Targeting abnormal ER stress responses in tumors: A new approach to cancer immunotherapy.

Oncoimmunology 2016 Mar 29;5(3):e1098802. Epub 2015 Oct 29.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

Cancers thrive under adverse conditions and simultaneously inhibit antitumor immunity. We recently found that endoplasmic reticulum (ER) stress responses driven by the IRE1α-XBP1 pathway not only promote cancer cell survival, but also provoke severe dendritic cell (DC) dysfunction in tumors. Targeting IRE1α-XBP1 represents a two-pronged approach to restrain malignant cells while eliciting concomitant antitumor immunity.
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http://dx.doi.org/10.1080/2162402X.2015.1098802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839339PMC
March 2016

Novel roles for XBP1 in hematopoietic development.

Cell Cycle 2016 07 8;15(13):1653-4. Epub 2016 Apr 8.

a Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College , New York , NY , USA.

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http://dx.doi.org/10.1080/15384101.2016.1172470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957590PMC
July 2016

Molecular Pathways: Immunosuppressive Roles of IRE1α-XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment.

Clin Cancer Res 2016 05 15;22(9):2121-6. Epub 2016 Mar 15.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.

The endoplasmic reticulum (ER) is a massive cytoplasmic membrane network that functions primarily to ensure proper folding and posttranslational modification of newly synthesized secreted and transmembrane proteins. Abnormal accumulation of unfolded proteins in this organelle causes a state of "ER stress," which is a hallmark feature of various diseases, including cancer, neurodegeneration, and metabolic dysfunction. Cancer cells exploit the IRE1α-XBP1 arm of the ER stress response to efficiently adjust their protein-folding capacity and ensure survival under hostile tumor microenvironmental conditions. However, we recently found that dendritic cells (DC) residing in the ovarian cancer microenvironment also experience sustained ER stress and demonstrate persistent activation of the IRE1α-XBP1 pathway. This previously unrecognized process disrupts metabolic homeostasis and antigen-presenting capacity in DCs, thereby crippling their natural ability to support the protective functions of infiltrating antitumor T cells. In this review, we briefly discuss some of the mechanisms that fuel ER stress in tumor-associated DCs, the biologic processes altered by aberrant IRE1α-XBP1 signaling in these innate immune cells, and the unique immunotherapeutic potential of targeting this pathway in cancer hosts. Clin Cancer Res; 22(9); 2121-6. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854763PMC
May 2016

MEKK2 mediates an alternative β-catenin pathway that promotes bone formation.

Proc Natl Acad Sci U S A 2016 Mar 16;113(9):E1226-35. Epub 2016 Feb 16.

Department of Pathology and Laboratory Medicine Weill Cornell Medicine, New York, NY 10065;

Proper tuning of β-catenin activity in osteoblasts is required for bone homeostasis, because both increased and decreased β-catenin activity have pathologic consequences. In the classical pathway for β-catenin activation, stimulation with WNT ligands suppresses constitutive phosphorylation of β-catenin by glycogen synthase kinase 3β, preventing β-catenin ubiquitination and proteasomal degradation. Here, we have found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2 or MEKK2) mediates an alternative pathway for β-catenin activation in osteoblasts that is distinct from the canonical WNT pathway. FGF2 activates MEKK2 to phosphorylate β-catenin at serine 675, promoting recruitment of the deubiquitinating enzyme, ubiquitin-specific peptidase 15 (USP15). USP15 in turn prevents the basal turnover of β-catenin by inhibiting its ubiquitin-dependent proteasomal degradation, thereby enhancing WNT signaling. Analysis of MEKK2-deficient mice and genetic interaction studies between Mekk2- and β-catenin-null alleles confirm that this pathway is an important physiologic regulator of bone mass in vivo. Thus, an FGF2/MEKK2 pathway mediates an alternative nonclassical pathway for β-catenin activation, and this pathway is a key regulator of bone formation by osteoblasts.
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http://dx.doi.org/10.1073/pnas.1600813113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780654PMC
March 2016

Regulation of Memory Formation by the Transcription Factor XBP1.

Cell Rep 2016 Feb 4;14(6):1382-1394. Epub 2016 Feb 4.

Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address:

Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer's disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.
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http://dx.doi.org/10.1016/j.celrep.2016.01.028DOI Listing
February 2016

William Erwin Paul (1936-2015).

Cell 2015 Oct;163(3):529-30

Howard Hughes Medical Institute, Department of Microbiology and Immunology, Institute of Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94304, USA

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http://dx.doi.org/10.1016/j.cell.2015.10.024DOI Listing
October 2015

XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease.

PLoS Genet 2015 Sep 15;11(9):e1005505. Epub 2015 Sep 15.

Murdoch Childrens Research Institute, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.

Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-β activity in MCDS chondrocytes may offer therapeutic opportunities.
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http://dx.doi.org/10.1371/journal.pgen.1005505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651170PMC
September 2015

An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease.

Sci Transl Med 2015 Aug;7(300):300ra128

Center for Regenerative Therapeutics, Biomedical Research Institute, Brigham and Women's Hospital, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA. Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139, USA. Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.
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http://dx.doi.org/10.1126/scitranslmed.aaa5657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825054PMC
August 2015

The transcription factor XBP1 is selectively required for eosinophil differentiation.

Nat Immunol 2015 Aug 6;16(8):829-37. Epub 2015 Jul 6.

1] Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA. [2] Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.

The transcription factor XBP1 has been linked to the development of highly secretory tissues such as plasma cells and Paneth cells, yet its function in granulocyte maturation has remained unknown. Here we discovered an unexpectedly selective and absolute requirement for XBP1 in eosinophil differentiation without an effect on the survival of basophils or neutrophils. Progenitors of myeloid cells and eosinophils selectively activated the endoribonuclease IRE1α and spliced Xbp1 mRNA without inducing parallel endoplasmic reticulum (ER) stress signaling pathways. Without XBP1, nascent eosinophils exhibited massive defects in the post-translational maturation of key granule proteins required for survival, and these unresolvable structural defects fed back to suppress critical aspects of the transcriptional developmental program. Hence, we present evidence that granulocyte subsets can be distinguished by their differential reliance on secretory-pathway homeostasis.
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http://dx.doi.org/10.1038/ni.3225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577297PMC
August 2015

IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection.

Nat Commun 2015 Jun 25;6:7562. Epub 2015 Jun 25.

Department of Medicine, Weill Cornell Medical College, Cornell University, 1300 York Avenue, New York, New York 10065, USA.

Initial events after exposure determine HIV-1 disease progression, underscoring a critical need to understand host mechanisms that interfere with initial viral replication. Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity. Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells. IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling. Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression. Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T-cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo.
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http://dx.doi.org/10.1038/ncomms8562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481879PMC
June 2015

ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.

Cell 2015 Jun 11;161(7):1527-38. Epub 2015 Jun 11.

Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address:

Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.
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http://dx.doi.org/10.1016/j.cell.2015.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580135PMC
June 2015

Tetraspanin CD9 and ectonucleotidase CD73 identify an osteochondroprogenitor population with elevated osteogenic properties.

Development 2015 Feb 6;142(3):438-43. Epub 2015 Jan 6.

Abide Therapeutics, San Diego, CA 92121, USA.

Cell-based bone regeneration strategies offer promise for traumatic bone injuries, congenital defects, non-union fractures and other skeletal pathologies. Postnatal bone remodeling and fracture healing provide evidence that an osteochondroprogenitor cell is present in adult life that can differentiate to remodel or repair the fractured bone. However, cell-based skeletal repair in the clinic is still in its infancy, mostly due to poor characterization of progenitor cells and lack of knowledge about their in vivo behavior. Here, we took a combined approach of high-throughput screening, flow-based cell sorting and in vivo transplantation to isolate markers that identify osteochondroprogenitor cells. We show that the presence of tetraspanin CD9 enriches for osteochondroprogenitors within CD105(+) mesenchymal cells and that these cells readily form bone upon transplantation. In addition, we have used Thy1.2 and the ectonucleotidase CD73 to identify subsets within the CD9(+) population that lead to endochondral or intramembranous-like bone formation. Utilization of this unique cell surface phenotype to enrich for osteochondroprogenitor cells will allow for further characterization of the molecular mechanisms that regulate their osteogenic properties.
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http://dx.doi.org/10.1242/dev.113571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302994PMC
February 2015

Endoplasmic reticulum stress in immunity.

Annu Rev Immunol 2015 10;33:107-38. Epub 2014 Dec 10.

Department of Medicine, Weill Cornell Medical College, New York, NY 10065; email: ,

Immune responses occur in the midst of a variety of cellular stresses that can severely perturb endoplasmic reticulum (ER) function. The unfolded protein response is a three-pronged signaling axis dedicated to preserving ER homeostasis. In this review, we highlight many important and emerging functional roles for ER stress in immunity, focusing on how the bidirectional cross talk between immunological processes and basic cell biology leads to pleiotropic signaling outcomes and enhanced sensitivity to inflammatory stimuli. We also discuss how dysregulated ER stress responses can provoke many diseases, including autoimmunity, firmly positioning the unfolded protein response as a major therapeutic target in human disease.
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http://dx.doi.org/10.1146/annurev-immunol-032414-112116DOI Listing
December 2015

p38α MAPK is required for tooth morphogenesis and enamel secretion.

J Biol Chem 2015 Jan 18;290(1):284-95. Epub 2014 Nov 18.

the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065,

An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678-27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38α MAPK in ectodermal appendages using K14-cre mice (p38α(K14) mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38α, expression of amelogenin and β4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.
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http://dx.doi.org/10.1074/jbc.M114.599274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281732PMC
January 2015

Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet-/-.Rag2-/- (TRUC) mice.

Proc Natl Acad Sci U S A 2014 Jun 9;111(25):E2559-66. Epub 2014 Jun 9.

Weill Cornell Medical College, New York, NY 10065

T-bet(-/-).Rag2(-/-) (TRUC) mice spontaneously develop microbiota-driven, TNF-mediated large bowel inflammation that resembles human ulcerative colitis. We show here that IL-23 and IL-1-dependent secretion of IL-17A by innate lymphoid cells (ILCs; defined as CD45(+)lin(-)Thy1(hi)NKp46(-)) is a second critical pathway in this model. Using an in vitro coculture system of bone marrow-derived dendritic cells (DCs) and freshly isolated FACS-purified ILCs, we demonstrate that IL-23 and IL-1 secreted by DCs in response to microbial stimulation work together to induce IL-17A production by ILCs. TNF is not required for IL-17A secretion by ILCs in vitro but synergizes with IL-17A to induce the expression of neutrophil-attracting chemokines. Upstream, activation of the IL-23/IL-17A axis is regulated by nucleotide-binding oligomerization domain containing (Nod)/receptor-interacting serine-threonine kinase 2 (Ripk2) signals in DCs. Genetic ablation of the Nod/Ripk2 signaling pathway protects TRUC mice from developing colitis without affecting the colitogenicity of the intestinal microbiota. Our data provide insight into the complex network of interactions between IL-17A-secreting ILCs and other components of the innate immune system in the development of colitis.
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http://dx.doi.org/10.1073/pnas.1408540111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078823PMC
June 2014

XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.

Nature 2014 Apr 23;508(7494):103-107. Epub 2014 Mar 23.

Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
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http://dx.doi.org/10.1038/nature13119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105133PMC
April 2014