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619 results on '"Ueberheide, Beatrix"'

103. Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM

Author

Lanz, Tobias V, primary, Brewer, R Camille, additional, Ho, Peggy P, additional, Jude, Kevin M, additional, Fernandez, Daniel, additional, Moon, Jae-Seung, additional, Fernandes, Ricardo A, additional, Gomez, Alejandro M, additional, Nadj, Gabriel-Stefan, additional, Bartley, Christopher M, additional, Schubert, Ryan D, additional, Hawes, Isobel A, additional, Vazquez, Sara E, additional, Iyer, Manasi, additional, Zuchero, J Bradley, additional, Teegen, Bianca, additional, Dunn, Jeffrey E, additional, Lock, Christopher B, additional, Kipp, Lucas B, additional, Cotham, Victoria C, additional, Ueberheide, Beatrix M, additional, Aftab, Blake T, additional, Anderson, Mark S, additional, DeRisi, Joseph L, additional, Wilson, Michael R, additional, Bashford-Rogers, Rachael JM, additional, Platten, Michael, additional, Garcia, K Christopher, additional, Steinman, Lawrence, additional, and Robinson, William H, additional

Published
2022
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104. Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Author

Chang, Chewei Anderson, primary, Jen, Jayu, additional, Jiang, Shaowen, additional, Sayad, Azin, additional, Mer, Arvind Singh, additional, Brown, Kevin R., additional, Nixon, Allison M.L., additional, Dhabaria, Avantika, additional, Tang, Kwan Ho, additional, Venet, David, additional, Sotiriou, Christos, additional, Deng, Jiehui, additional, Wong, Kwok-kin, additional, Adams, Sylvia, additional, Meyn, Peter, additional, Heguy, Adriana, additional, Skok, Jane A., additional, Tsirigos, Aristotelis, additional, Ueberheide, Beatrix, additional, Moffat, Jason, additional, Singh, Abhyudai, additional, Haibe-Kains, Benjamin, additional, Khodadadi-Jamayran, Alireza, additional, and Neel, Benjamin G., additional

Published
2021
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105. UvrD facilitates DNA repair by pulling RNA polymerase backwards

Author

Epshtein, Vitaly, Kamarthapu, Venu, McGary, Katelyn, Svetlov, Vladimir, Ueberheide, Beatrix, Proshkin, Sergey, Mironov, Alexander, and Nudler, Evgeny

Subjects
RNA polymerases -- Physiological aspects, DNA repair -- Research, Genetic research, Genetic transcription -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

UvrD helicase is required for nucleotide excision repair, although its role in this process is not well defined. Here we show that Escherichia coli UvrD binds RNA polymerase during transcription elongation and, using its helicase/translocase activity, forces RNA polymerase to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNA polymerase, allowing nucleotide excision repair enzymes to gain access to sites of damage. Our results establish UvrD as a bona fide transcription elongation factor that contributes to genomic integrity by resolving conflicts between transcription and DNA repair complexes. Furthermore, we show that the elongation factor NusA cooperates with UvrD in coupling transcription to DNA repair by promoting backtracking and recruiting nucleotide excision repair enzymes to exposed lesions. Because backtracking is a shared feature of all cellular RNA polymerases, we propose that this mechanism enables RNA polymerases to function as global DNA damage scanners in bacteria and eukaryotes., Nucleotide excision repair (NER) is the most versatile and evolutionarily conserved mechanism used by prokaryotic and eukaryotic cells to repair diverse types of DNA lesions (1,2). In bacteria, the general [...]

Published
2014
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106. Brain molecular mechanisms in Rasmussen encephalitis.

Author

Leitner, Dominique F., Lin, Ziyan, Sawaged, Zacharia, Kanshin, Evgeny, Friedman, Daniel, Devore, Sasha, Ueberheide, Beatrix, Chang, Julia W., Mathern, Gary W., Anink, Jasper J., Aronica, Eleonora, Wisniewski, Thomas, and Devinsky, Orrin

Subjects
EPILEPSY, KILLER cells, ENCEPHALITIS, HLA histocompatibility antigens, FALSE discovery rate, SURGERY
Abstract

Objective: This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non‐RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Methods: Frozen brain tissue (ages = 2–19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p <.05) and label‐free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. Results: WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA‐DRB1, HLA‐DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10−6, z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10−13, z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10−13, z = 5.61). Proteomics detected fewer altered targets. Significance: In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow‐up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression. [ABSTRACT FROM AUTHOR]

Published
2023
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107. Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leads

Author

Ramiro, Iris Bea. L., primary, Bjørn-Yoshimoto, Walden E., additional, Imperial, Julita S., additional, Gajewiak, Joanna, additional, Watkins, Maren, additional, Taylor, Dylan, additional, Resager, William, additional, Ueberheide, Beatrix, additional, Bräuner-Osborne, Hans, additional, Whitby, Frank G., additional, Hill, Christopher P., additional, Martin, Laurent F., additional, Patwardhan, Amol, additional, Concepcion, Gisela P., additional, Olivera, Baldomero M., additional, and Safavi-Hemami, Helena, additional

Published
2021
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108. Targeting the Atf7ip–Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity

Author

Hu, Hai, primary, Khodadadi-Jamayran, Alireza, additional, Dolgalev, Igor, additional, Cho, Hyunwoo, additional, Badri, Sana, additional, Chiriboga, Luis A., additional, Zeck, Briana, additional, Lopez De Rodas Gregorio, Miguel, additional, Dowling, Catríona M., additional, Labbe, Kristen, additional, Deng, Jiehui, additional, Chen, Ting, additional, Zhang, Hua, additional, Zappile, Paul, additional, Chen, Ze, additional, Ueberheide, Beatrix, additional, Karatza, Angeliki, additional, Han, Han, additional, Ranieri, Michela, additional, Tang, Sittinon, additional, Jour, George, additional, Osman, Iman, additional, Sucker, Antje, additional, Schadendorf, Dirk, additional, Tsirigos, Aristotelis, additional, Schalper, Kurt A., additional, Velcheti, Vamsidhar, additional, Huang, Hsin-yi, additional, Jin, Yujuan, additional, Ji, Hongbin, additional, Poirier, John T., additional, Li, Fei, additional, and Wong, Kwok-Kin, additional

Published
2021
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109. Abstract 41: Tumor resistance to CDK4/6 inhibitors and degraders determined by the expression state of CDK6

Author

Wu, Xuewei, primary, Yang, Xiaobao, additional, Xiong, Yan, additional, Li, Ruitong, additional, Ito, Takahiro, additional, Ahmed, Tamer, additional, Karoulia, Zoi, additional, Adamopoulos, Christos, additional, Wang, Hong, additional, Wang, Li, additional, Xie, Ling, additional, Ueberheide, Beatrix, additional, Aaronson, Stuart, additional, Chen, Xian, additional, Sellers, William, additional, Buchanan, Sean, additional, Jin, Jian, additional, and Poulikakos, Poulikos I., additional

Published
2021
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111. Proteomics and Transcriptomics of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Patients

Author

Leitner, Dominique F., primary, Mills, James D., additional, Pires, Geoffrey, additional, Faustin, Arline, additional, Drummond, Eleanor, additional, Kanshin, Evgeny, additional, Nayak, Shruti, additional, Askenazi, Manor, additional, Verducci, Chloe, additional, Chen, Bei Jun, additional, Janitz, Michael, additional, Anink, Jasper J., additional, Baayen, Johannes C., additional, Idema, Sander, additional, van Vliet, Erwin A., additional, Devore, Sasha, additional, Friedman, Daniel, additional, Diehl, Beate, additional, Scott, Catherine, additional, Thijs, Roland, additional, Wisniewski, Thomas, additional, Ueberheide, Beatrix, additional, Thom, Maria, additional, Aronica, Eleonora, additional, and Devinsky, Orrin, additional

Published
2021
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113. Proteomic differences in the hippocampus and cortex of epilepsy brain tissue

Author

Pires, Geoffrey, primary, Leitner, Dominique, additional, Drummond, Eleanor, additional, Kanshin, Evgeny, additional, Nayak, Shruti, additional, Askenazi, Manor, additional, Faustin, Arline, additional, Friedman, Daniel, additional, Debure, Ludovic, additional, Ueberheide, Beatrix, additional, Wisniewski, Thomas, additional, and Devinsky, Orrin, additional

Published
2021
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114. Geranylgeranylated SCFFBXO10regulates selective outer mitochondrial membrane proteostasis and function

Author

Bhat, Sameer Ahmed, Vasi, Zahra, Jiang, Liping, Selvaraj, Shruthi, Ferguson, Rachel, Salarvand, Sanaz, Gudur, Anish, Adhikari, Ritika, Castillo, Veronica, Ismail, Hagar, Dhabaria, Avantika, Ueberheide, Beatrix, and Kuchay, Shafi

Abstract

Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.

Published
2024
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117. Quantitative phosphoproteomic analysis reveals involvement of PD-1 in multiple T cell functions

Author

Tocheva, Anna S., primary, Peled, Michael, additional, Strazza, Marianne, additional, Adam, Kieran R., additional, Lerrer, Shalom, additional, Nayak, Shruti, additional, Azoulay-Alfaguter, Inbar, additional, Foster, Connor J.R., additional, Philips, Elliot A., additional, Neel, Benjamin G., additional, Ueberheide, Beatrix, additional, and Mor, Adam, additional

Published
2020
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122. Protein Quantitation Using Mass Spectrometry

Author

Zhang, Guoan, primary, Ueberheide, Beatrix M., additional, Waldemarson, Sofia, additional, Myung, Sunnie, additional, Molloy, Kelly, additional, Eriksson, Jan, additional, Chait, Brian T., additional, Neubert, Thomas A., additional, and Fenyö, David, additional

Published
2010
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123. The amyloid plaque proteome in early onset Alzheimer's disease and Down syndrome.

Author

Drummond, Eleanor, Kavanagh, Tomas, Pires, Geoffrey, Marta-Ariza, Mitchell, Kanshin, Evgeny, Nayak, Shruti, Faustin, Arline, Berdah, Valentin, Ueberheide, Beatrix, and Wisniewski, Thomas

Subjects
DOWN syndrome, ALZHEIMER'S disease, AMYLOID plaque, EZRIN
Abstract

Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC–MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD. [ABSTRACT FROM AUTHOR]

Published
2022
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126. Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Author

Chang, Che-wei Anderson, primary, Jen, Jayu, additional, Jiang, Shaowen, additional, Sayad, Azin, additional, Mer, Arvind Singh, additional, Brown, Kevin R., additional, Nixon, Allison, additional, Dhabaria, Avantika, additional, Tang, Kwan Ho, additional, Venet, David, additional, Sotiriou, Christos, additional, Deng, Jiehue, additional, Wong, Kwok-kin, additional, Adams, Sylvia, additional, Meyn, Peter, additional, Heguy, Adriana, additional, Skok, Jane, additional, Tsirigos, Aristotelis, additional, Ueberheide, Beatrix, additional, Moffat, Jason, additional, Singh, Abhyudai, additional, Haibe-Kains, Benjamin, additional, Khodadadi-Jamayran, Alireza, additional, and Neel, Benjamin G., additional

Published
2020
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128. Proteomic and Transcriptomic Analyses of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Cases

Author

Leitner, Dominique F., primary, Mills, James D., additional, Pires, Geoffrey, additional, Faustin, Arline, additional, Drummond, Eleanor, additional, Kanshin, Evgeny, additional, Nayak, Shruti, additional, Askenazi, Manor, additional, Verducci, Chloe, additional, Chen, Bei Jun, additional, Janitz, Michael, additional, Anink, Jasper J., additional, Baayen, Johannes C., additional, Idema, Sander, additional, van Vliet, Erwin A., additional, Devore, Sasha, additional, Friedman, Daniel, additional, Diehl, Beate, additional, Scott, Catherine, additional, Thijs, Roland, additional, Wisniewski, Thomas, additional, Ueberheide, Beatrix, additional, Thom, Maria, additional, Aronica, Eleonora, additional, and Devinsky, Orrin, additional

Published
2020
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129. Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Author

Pires, Geoffrey, primary, Leitner, Dominique, additional, Drummond, Eleanor, additional, Kanshin, Evgeny, additional, Nayak, Shruti, additional, Askenazi, Manor, additional, Faustin, Arline, additional, Friedman, Daniel, additional, Debure, Ludovic, additional, Ueberheide, Beatrix, additional, Wisniewski, Thomas, additional, and Devinsky, Orrin, additional

Published
2020
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133. Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, additional, Wong, Eitan, additional, Galán-Echevarría, Francisco, additional, Von-Itter, Richard, additional, Rose, Indigo, additional, Blumenberg, Lili, additional, Floristán, Alfredo, additional, Tranos, James, additional, Argibay, Diana, additional, Chen, Jenny, additional, Dhabaria, Avantika, additional, de Miera Sainz de Vega, Eleazar, additional, Rogers, Robert, additional, Zaim-Wadghiri, Youssef, additional, Mathews, Paul, additional, Osman, Iman, additional, Ruggles, Kelly, additional, Ueberheide, Beatrix, additional, Liddelow, Shane A., additional, DeMattos, Ronald, additional, Li, Yue Ming, additional, Schneider, Robert J., additional, and Hernando, Eva, additional

Published
2019
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134. Proteomic Characterization of Senescent Laryngeal Adductor and Plantaris Hindlimb Muscles.

Author

Shembel, Adrianna C., Kanshin, Evgeny, Ueberheide, Beatrix, and Johnson, Aaron M.

Abstract

Objectives: The goals of this study were to 1) compare global protein expression in muscles of the larynx and hindlimb and 2) investigate differences in protein expression between aged and nonaged muscle using label‐free global proteomic profiling methods. Methods: Liquid chromatography‐mass spectrometry (LC‐MS/MS) analysis was performed on thyroarytenoid intrinsic laryngeal muscle and plantaris hindlimb muscle from 10 F344xBN F1 male rats (5 old and 5 young). Protein expression was compared and pathway enrichment analysis performed for each muscle type (larynx and limb) and age group (old and young muscle). Results: Over 1,000 proteins were identified in common across both muscle types and age groups using LC‐MS/MS analysis. Significant age‐related differences were seen across 107 proteins in plantaris hindlimb and in 19 proteins in thyroarytenoid laryngeal muscle. Bioinformatic and enrichment analysis demonstrated protein differences between the hindlimb and larynx may relate to immune and stress redox responses and RNA repair. Conclusion: There are clear differences in protein expressions between the laryngeal and hindlimb skeletal muscles. Initial analysis suggests differences between the two muscle groups may relate to stress responses and repair mechanisms. Age‐related changes in the thyroarytenoid appear to be less obvious than in the plantaris. Further in‐depth study is needed to elucidate how aging affects protein expression in the laryngeal muscles. Level of Evidence: NA Laryngoscope, 132:148–155, 2022 [ABSTRACT FROM AUTHOR]

Published
2022
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139. Characterization of the First Conotoxin from Conus ateralbus, a Vermivorous Cone Snail from the Cabo Verde Archipelago

Author

Neves, Jorge L. B., primary, Imperial, Julita S., additional, Morgenstern, David, additional, Ueberheide, Beatrix, additional, Gajewiak, Joanna, additional, Antunes, Agostinho, additional, Robinson, Samuel D., additional, Espino, Samuel, additional, Watkins, Maren, additional, Vasconcelos, Vitor, additional, and Olivera, Baldomero M., additional

Published
2019
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143. Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1

Author

Lignitto, Luca, primary, LeBoeuf, Sarah E., additional, Homer, Harrison, additional, Jiang, Shaowen, additional, Askenazi, Manor, additional, Karakousi, Triantafyllia R., additional, Pass, Harvey I., additional, Bhutkar, Arjun J., additional, Tsirigos, Aristotelis, additional, Ueberheide, Beatrix, additional, Sayin, Volkan I., additional, Papagiannakopoulos, Thales, additional, and Pagano, Michele, additional

Published
2019
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146. USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Author

Jin, Qi, primary, Martinez, Carlos A., additional, Arcipowski, Kelly M., additional, Zhu, Yixing, additional, Gutierrez-Diaz, Blanca T., additional, Wang, Kenneth K., additional, Johnson, Megan R., additional, Volk, Andrew G., additional, Wang, Feng, additional, Wu, Jian, additional, Grove, Charles, additional, Wang, Hui, additional, Sokirniy, Ivan, additional, Thomas, Paul M., additional, Goo, Young Ah, additional, Abshiru, Nebiyu A., additional, Hijiya, Nobuko, additional, Peirs, Sofie, additional, Vandamme, Niels, additional, Berx, Geert, additional, Goosens, Steven, additional, Marshall, Stacy A., additional, Rendleman, Emily J., additional, Takahashi, Yoh-hei, additional, Wang, Lu, additional, Rawat, Radhika, additional, Bartom, Elizabeth T., additional, Collings, Clayton K., additional, Van Vlierberghe, Pieter, additional, Strikoudis, Alexandros, additional, Kelly, Stephen, additional, Ueberheide, Beatrix, additional, Mantis, Christine, additional, Kandela, Irawati, additional, Bourquin, Jean-Pierre, additional, Bornhauser, Beat, additional, Serafin, Valentina, additional, Bresolin, Silvia, additional, Paganin, Maddalena, additional, Accordi, Benedetta, additional, Basso, Giuseppe, additional, Kelleher, Neil L., additional, Weinstock, Joseph, additional, Kumar, Suresh, additional, Crispino, John D., additional, Shilatifard, Ali, additional, and Ntziachristos, Panagiotis, additional

Published
2019
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147. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Author

Lanz, Tobias V., Brewer, R. Camille, Ho, Peggy P., Moon, Jae-Seung, Jude, Kevin M., Fernandez, Daniel, Fernandes, Ricardo A., Gomez, Alejandro M., Nadj, Gabriel-Stefan, Bartley, Christopher M., Schubert, Ryan D., Hawes, Isobel A., Vazquez, Sara E., Iyer, Manasi, Zuchero, J. Bradley, Teegen, Bianca, Dunn, Jeffrey E., Lock, Christopher B., Kipp, Lucas B., Cotham, Victoria C., Ueberheide, Beatrix M., Aftab, Blake T., Anderson, Mark S., DeRisi, Joseph L., Wilson, Michael R., Bashford-Rogers, Rachael J. M., Platten, Michael, Garcia, K. Christopher, Steinman, Lawrence, and Robinson, William H.

Abstract

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein–Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1–peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1–GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

Published
2022
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148. The γδ IEL effector API5 masks genetic susceptibility to Paneth cell death

Author

Matsuzawa-Ishimoto, Yu, Yao, Xiaomin, Koide, Akiko, Ueberheide, Beatrix M., Axelrad, Jordan E., Reis, Bernardo S., Parsa, Roham, Neil, Jessica A., Devlin, Joseph C., Rudensky, Eugene, Dewan, M. Zahidunnabi, Cammer, Michael, Blumberg, Richard S., Ding, Yi, Ruggles, Kelly V., Mucida, Daniel, Koide, Shohei, and Cadwell, Ken

Abstract

Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn’s disease, a major type of inflammatory bowel disease1–7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn’s disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte–epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.

Published
2022
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150. GENE-14. DNA METHYLATION AND PROTEOMIC ALTERATIONS IDENTIFY HISTOLOGICALLY-DEFINED TUMOR CELL POPULATIONS AND CHARACTERIZE INTRATUMOR HETEROGENEITY IN GLIOBLASTOMA

Author

Gagner, Jean-Pierre, primary, Kamen, Scott, additional, Nayak, Shruti, additional, Serrano, Jonathan, additional, Vasudevaraja, Varshini, additional, Bledea, Ramona, additional, Ueberheide, Beatrix, additional, Snuderl, Matija, additional, Lechpammer, Mirna, additional, and Zagzag, David, additional

Published
2018
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