Honglin Jiang, Ryan K Muir, R. Gonciarz, A. Olshen, I. Yeh, B. Hann, Ning Zhao, Yung-hua Wang, S. Behr, J. Korkola, M. Evans, E. Collisson, A. Renslo
{"title":"Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors","authors":"Honglin Jiang, Ryan K Muir, R. Gonciarz, A. Olshen, I. Yeh, B. Hann, Ning Zhao, Yung-hua Wang, S. Behr, J. Korkola, M. Evans, E. Collisson, A. Renslo","doi":"10.1084/jem.20210739","DOIUrl":"https://doi.org/10.1084/jem.20210739","url":null,"abstract":"Jiang et al. report that oncogenic KRAS signaling induces ferrous iron (Fe2+) accumulation throughout mutant KRAS-mediated transformation. Converting an FDA-approved MEK inhibitor into a ferrous iron–activatable drug conjugate (FeADC) achieves potent MAPK blockade in tumor cells with superior systemic tolerability.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83369557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Giordano, M. Luciani, F. Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, A. Migliara, Sara Valsoni, M. Genua, M. Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, S. Giliani, S. Orcesi, E. Fazzi, Renato Ostuni, Angelo D’Alessandro, Raffaella Di Micco, I. Merelli, A. Lombardo, Martin A. M. Reijns, N. Gromak, A. Gritti, A. Kajaste-Rudnitski
{"title":"DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes","authors":"A. Giordano, M. Luciani, F. Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, A. Migliara, Sara Valsoni, M. Genua, M. Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, S. Giliani, S. Orcesi, E. Fazzi, Renato Ostuni, Angelo D’Alessandro, Raffaella Di Micco, I. Merelli, A. Lombardo, Martin A. M. Reijns, N. Gromak, A. Gritti, A. Kajaste-Rudnitski","doi":"10.1084/jem.20211121","DOIUrl":"https://doi.org/10.1084/jem.20211121","url":null,"abstract":"Giordano et al. establish human AGS iPSC-based models of TREX1 or RNASEH2B deficiencies. They uncover DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes that can be uncoupled from aberrant type I IFN responses and identify novel targets to curtail AGS neuroinflammation.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73038358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Martín-Fernández, S. Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, F. Vuillier, Lina Franklin, F. Ailal, Alice Muglia Amancio, L. Malle, C. Gruber, I. Benhsaien, J. Altman, J. Taft, C. Deswarte, Manon Roynard, A. Nieto-Patlán, K. Moriya, J. Rosain, N. Boddaert, A. Bousfiha, Y. Crow, Dragana Jankovic, A. Sher, J. Casanova, S. Pellegrini, J. Bustamante, D. Bogunovic
{"title":"A partial form of inherited human USP18 deficiency underlies infection and inflammation","authors":"M. Martín-Fernández, S. Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, F. Vuillier, Lina Franklin, F. Ailal, Alice Muglia Amancio, L. Malle, C. Gruber, I. Benhsaien, J. Altman, J. Taft, C. Deswarte, Manon Roynard, A. Nieto-Patlán, K. Moriya, J. Rosain, N. Boddaert, A. Bousfiha, Y. Crow, Dragana Jankovic, A. Sher, J. Casanova, S. Pellegrini, J. Bustamante, D. Bogunovic","doi":"10.1084/jem.20211273","DOIUrl":"https://doi.org/10.1084/jem.20211273","url":null,"abstract":"Martin-Fernandez et al. describe patients with partial USP18 deficiency, which underlies both type I interferonopathy and Mendelian susceptibility to mycobacterial disease (MSMD). This work delineates the lack of negative regulation of the IFN-I signaling pathway leading to depression of the IFN-γ–IL12 loop as a cause of MSMD.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81002460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Z. Fang, Yi Zhang, Zhaoqin Zhu, Cong Wang, Yao Hu, Xiuhua Peng, Dandan Zhang, Jun Zhao, Bisheng Shi, Zhongliang Shen, Min Wu, Chunhua Xu, Jieliang Chen, Xiaohui Zhou, Youhua Xie, Hui Yu, Xiaonan Zhang, Jianhua Li, Yun-wen Hu, M. Kozlowski, A. Bertoletti, Zhenghong Yuan
{"title":"Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV","authors":"Z. Fang, Yi Zhang, Zhaoqin Zhu, Cong Wang, Yao Hu, Xiuhua Peng, Dandan Zhang, Jun Zhao, Bisheng Shi, Zhongliang Shen, Min Wu, Chunhua Xu, Jieliang Chen, Xiaohui Zhou, Youhua Xie, Hui Yu, Xiaonan Zhang, Jianhua Li, Yun-wen Hu, M. Kozlowski, A. Bertoletti, Zhenghong Yuan","doi":"10.1084/jem.20211838","DOIUrl":"https://doi.org/10.1084/jem.20211838","url":null,"abstract":"HBV exposure in children usually causes chronic infection, and HBsAg-specific CD8+ T cells are rarely detected in this situation. We find that mMDSCs, cross-presenting HBsAg, migrate to the thymus and eliminate HBsAg-specific CD8+ thymocytes, resulting in a specific tolerance to HBV.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82016902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maxence Cornille, Stéphanie Moriceau, R. Khonsari, Y. Heuzé, L. Loisay, Valérie Boitez, A. Morice, Éric Arnaud, C. Collet, M. Bensidhoum, N. Kaci, N. Boddaert, G. Paternoster, T. Rauschendorfer, Sabine Werner, S. Mansour, F. Di Rocco, F. Oury, L. Legeai-Mallet
{"title":"FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model","authors":"Maxence Cornille, Stéphanie Moriceau, R. Khonsari, Y. Heuzé, L. Loisay, Valérie Boitez, A. Morice, Éric Arnaud, C. Collet, M. Bensidhoum, N. Kaci, N. Boddaert, G. Paternoster, T. Rauschendorfer, Sabine Werner, S. Mansour, F. Di Rocco, F. Oury, L. Legeai-Mallet","doi":"10.1084/jem.20201879","DOIUrl":"https://doi.org/10.1084/jem.20201879","url":null,"abstract":"FGFR3 gain-of-function mutation leads to learning and memory impairments independently of skull abnormalities. Cornille et al. suggest that modulation of the FGFR3 signaling pathway might be of value for treating the neurological and cognitive impairments observed in craniosynostosis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86358329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Lorin, Ignacio Fernández, Guillemette Masse-Ranson, M. Bouvin-Pley, Luis M Molinos-Albert, C. Planchais, Thierry Hieu, G. Péhau-Arnaudet, D. Hrebík, Giulia Girelli-Zubani, O. Fiquet, F. Guivel-Benhassine, R. Sanders, B. Walker, O. Schwartz, J. Scheid, J. Dimitrov, P. Plevka, M. Braibant, M. Seaman, F. Bontems, J. D. Di Santo, F. Rey, H. Mouquet
{"title":"Epitope convergence of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a viremic controller","authors":"V. Lorin, Ignacio Fernández, Guillemette Masse-Ranson, M. Bouvin-Pley, Luis M Molinos-Albert, C. Planchais, Thierry Hieu, G. Péhau-Arnaudet, D. Hrebík, Giulia Girelli-Zubani, O. Fiquet, F. Guivel-Benhassine, R. Sanders, B. Walker, O. Schwartz, J. Scheid, J. Dimitrov, P. Plevka, M. Braibant, M. Seaman, F. Bontems, J. D. Di Santo, F. Rey, H. Mouquet","doi":"10.1084/jem.20212045","DOIUrl":"https://doi.org/10.1084/jem.20212045","url":null,"abstract":"This study identifies a trio of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a HIV-1 viremic controller that all target a unique viral site of vulnerability.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87226904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Dyck, Hannah Prendeville, Mathilde Raverdeau, Mieszko M. Wilk, Roisín M Loftus, A. Douglas, J. McCormack, Bruce Moran, M. Wilkinson, E. Mills, Michael Doughty, A. Fabre, Helen Heneghan, C. LeRoux, A. Hogan, Edward T. Chouchani, Donal O'Shea, Donal J Brennan, L. Lynch
{"title":"Correction: Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function","authors":"L. Dyck, Hannah Prendeville, Mathilde Raverdeau, Mieszko M. Wilk, Roisín M Loftus, A. Douglas, J. McCormack, Bruce Moran, M. Wilkinson, E. Mills, Michael Doughty, A. Fabre, Helen Heneghan, C. LeRoux, A. Hogan, Edward T. Chouchani, Donal O'Shea, Donal J Brennan, L. Lynch","doi":"10.1084/jem.2021004202072022c","DOIUrl":"https://doi.org/10.1084/jem.2021004202072022c","url":null,"abstract":"","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83592192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Bigley, Liping Yang, L. Kang, J. Saenz, F. Victorino, W. Yokoyama
{"title":"Disruption of thymic central tolerance by infection with murine roseolovirus induces autoimmune gastritis","authors":"T. Bigley, Liping Yang, L. Kang, J. Saenz, F. Victorino, W. Yokoyama","doi":"10.1084/jem.20211403","DOIUrl":"https://doi.org/10.1084/jem.20211403","url":null,"abstract":"Bigley et al. show that neonatal murine roseolovirus infection disrupts central tolerance. Autoimmunity arises later, in the absence of ongoing infection. This study provides evidence for a new mechanism by which viruses induce autoimmunity at a time remote from initial infection.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90615412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lea-Marie Jenster, Karl-Elmar Lange, S. Normann, Anja vom Hemdt, J. D. Wuerth, L. Schiffelers, Y. Tesfamariam, F. N. Gohr, Laura B. C. Klein, I. H. Kaltheuner, Dorothee Johanna Lapp, Jacob Mayer, Jonas Moecking, H. Ploegh, E. Latz, M. Geyer, B. Kümmerer, F. Schmidt
{"title":"P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection","authors":"Lea-Marie Jenster, Karl-Elmar Lange, S. Normann, Anja vom Hemdt, J. D. Wuerth, L. Schiffelers, Y. Tesfamariam, F. N. Gohr, Laura B. C. Klein, I. H. Kaltheuner, Dorothee Johanna Lapp, Jacob Mayer, Jonas Moecking, H. Ploegh, E. Latz, M. Geyer, B. Kümmerer, F. Schmidt","doi":"10.1101/2022.01.24.477423","DOIUrl":"https://doi.org/10.1101/2022.01.24.477423","url":null,"abstract":"Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals converge on the activation of p38 kinases to initiate human NLRP1 inflammasome assembly: UV irradiation and microbial molecules that initiate the ribotoxic stress response critically relied on the MAP3 kinase ZAKα to activate p38 and ultimately human NLRP1. Infection with insect-transmitted alphaviruses, including Semliki Forest, Ross River, and Chikungunya virus, also activated NLRP1 in a p38-dependent manner. In the absence on ZAKα, inflammasome assembly was maintained, although at reduced levels, indicating contribution of other upstream kinases. NLRP1 activation by direct nanobody-mediated ubiquitination was independent of p38 activity. Stimulation of p38 by overexpression of MAP2 kinases MKK3 or MKK6 is sufficient for NLRP1 activation, and NLRP1 is directly phosphorylated by p38. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80098460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ho-Sup Lee, Hao Sun, F. Lagarrigue, J. Fox, N. Sherman, A. Gingras, M. Ginsberg
{"title":"Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs","authors":"Ho-Sup Lee, Hao Sun, F. Lagarrigue, J. Fox, N. Sherman, A. Gingras, M. Ginsberg","doi":"10.1101/2021.09.24.461584","DOIUrl":"https://doi.org/10.1101/2021.09.24.461584","url":null,"abstract":"Rap1 GTPase drives assembly of the Mig-10/RIAM/lamellipodin–Integrin–Talin (MIT) complex that enables integrin-dependent lymphocyte functions. Here we used tandem affinity tag-based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (PTSN), a regulatory subunit of protein phosphatase 1, is a component of the complex. PTSN mediates de-phosphorylation of Rap1 thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes PTSN, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18-/- mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable to defective activation of integrins αLβ2 and α4β7. Ppp1r18-/- T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, PTSN enables lymphocyte integrin-mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of PTSN ameliorates T cell-mediated colitis. SUMMARY Phostensin, a protein phosphatase 1 regulatory subunit, supports lymphocyte integrin-dependent functions by mediating dephosphorylation of Rap1 to stabilize the MIT complex thereby enabling the population of peripheral lymphoid organs and T cell-mediated colitis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73599655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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