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[Science] 22 NOVEMBER 2013 VOL 342, ISSUE 6161, PAGES 901-1012 [Science] 22 NOVEMBER 2013 VOL 342, ISSUE 6161, PAGES 901-1012 [Science] 22 NOVEMBER 2013 VOL 342, ISSUE 6161, PAGES 901-1012 [Science] 22 NOVEMBER 2013 VOL 342, ISSUE 6161, PAGES 901-1012 [Science] 22 NOVEMBER 2013 VOL 342, ISSUE 6161, PAGES 901-1012 [Science Signaling] 19 NOVEMBER 2013 VOL 6, ISSUE 302 [Science Translational Medicine] 13 November 2013 VOL 5, ISSUE 211 USP10 inhibits genotoxic NF-κB activation by MCPIP1-facilitated deubiquitination of NEMO Jixiao Niu1,2, Yuling Shi1,2, Jingyan Xue2,3, Ruidong Miao4, Shengping Huang4, Tianyi Wang5, Jiong Wu3, Mingui Fu4 and Zhao-Hui Wu1,2 Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA Department of Breast Surgery, Cancer Hospital/Institute, Fudan University, Shanghai, China Department of Basic Medical Science, University of Missouri Kansas City, Kansas City, MO, USA Department of Infectious Disease and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA Correspondence to: Zhao-Hui Wu, Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, 19 South Manassas Street, Memphis, TN 38163, USA Tel.:+1 901 448 2612; Fax:+1 901 448 3910; E-mail: [email protected] Received 23 January 2013; Accepted 31 October 2013 DNA damage-induced activation of the transcription factor NF-κB plays an important role in the cellular response to genotoxic stress. However, uncontrolled NF-κB activation upon DNA damage may lead to deleterious consequences. Although the mechanisms mediating genotoxic NF-κB activation have been elucidated, how this signalling is terminated remains poorly understood. Here, we show that the CCCH-type zinc finger-containing protein MCPIP1 (monocyte chemotactic protein-1-induced protein-1; also known as ZC3H12A) is induced upon genotoxic treatment in an NF-κB-dependent manner. MCPIP1 upregulation reduces NEMO linear ubiquitylation, resulting in decreased activation of IKK and NF-κB. NEMO ubiquitylation is decreased through the deubiquitinase USP10, which interacts with NEMO via MCPIP1 upon genotoxic stress. USP10 association with NEMO leads to removal of NEMO-attached linear polyubiquitin chains and subsequent inhibition of the genotoxic NF-κB signalling cascade. Consistently, USP10 is required for MCPIP1mediated inhibition of genotoxic NF-κB activation and promotion of apoptosis. Thus, by mediating USP10dependent deubiquitination of NEMO, MCPIP1 induction serves as a negative feedback mechanism for attenuating genotoxic NF-κB activation. Keywords: DNA damage; MCPIP1; NEMO; ubiquitylation; USP10 Research Article Involvement of TGFβ-Induced Phosphorylation of the PTEN C-Terminus on TGFβInduced Acquisition of Malignant Phenotypes in Lung Cancer Cells Abstract Transforming growth factor β (TGFβ) derived from the tumor microenvironment induces malignant phenotypes such as epithelial-mesenchymal transition (EMT) and aberrant cell motility in lung cancers. TGFβ-induced translocation of β-catenin from E-cadherin complexes into the cytoplasm is involved in the transcription of EMT target genes. PTEN (phosphatase and tensin homologue deleted from chromosome 10) is known to exert phosphatase activity by binding to E-cadherin complexes via β-catenin, and recent studies suggest that phosphorylation of the PTEN C-terminus tail might cause loss of this PTEN phosphatase activity. However, whether TGFβ can modulate both β-catenin translocation and PTEN phosphatase activity via phosphorylation of the PTEN C-terminus remains elusive. Furthermore, the role of phosphorylation of the PTEN C-terminus in TGFβ-induced malignant phenotypes has not been evaluated. To investigate whether modulation of phosphorylation of the PTEN C-terminus can regulate malignant phenotypes, here we established lung cancer cells expressing PTEN protein with mutation of phosphorylation sites in the PTEN C-terminus (PTEN4A). We found that TGFβ stimulation yielded a two-fold increase in the phosphorylated -PTEN/PTEN ratio. Expression of PTEN4A repressed TGFβ-induced EMT and cell motility even after snail expression. Our data showed that PTEN4A might repress EMT through complete blockade of β-catenin translocation into the cytoplasm, besides the inhibitory effect of PTEN4A on TGFβ-induced activation of smadindependent signaling pathways. In a xenograft model, the tumor growth ratio was repressed in cells expressing PTEN4A. Taken together, these data suggest that phosphorylation sites in the PTEN C-terminus might be a therapeutic target for TGFβ-induced malignant phenotypes in lung cancer cells Characterization of Persistent Virus-Like Particles in Two Acetate-Fed Methanogenic Reactors I-Chieh Chien, John Scott Meschke, [...], John F. Ferguson Decorin Mimic Inhibits Vascular Smooth Muscle Proliferation and Migration Rebecca A. Scott, John E. Paderi, [...], Alyssa Panitch Integrating Structure to Protein-Protein Interaction Networks That Drive Metastasis to Brain and Lung in Breast Cancer H. Billur Engin, Emre Guney, [...], Attila Gursoy The Contribution of Lysosomotropism to Autophagy Perturbation Roshan Ashoor, Rolla Yafawi, [...], Shuyan Lu Streptococcal SpeB Cleaved PAR-1 Suppresses ERK Phosphorylation and Blunts Thrombin-Induced Platelet Aggregation Miriam Ender, Federica Andreoni, [...], Reto Andreas Schuepbach Role of RANKL (TNFSF11)-Dependent Osteopetrosis in the Dental Phenotype of Msx2 Null Mutant Mice Beatriz Castaneda, Yohann Simon, [...], Frédéric Lézot Ox-LDL Induces ER Stress and Promotes the adipokines Secretion in 3T3-L1 Adipocytes Yaqin Chen, Mingjie Chen, [...], Shuiping Zhao Pyruvate Administration Reduces Recurrent/Moderate Hypoglycemia-Induced Cortical Neuron Death in Diabetic Rats Bo Young Choi, Jin Hee Kim, [...], Sang Won Suh Proteinuria Independently Predicts Unfavorable Outcome of Ischemic Stroke Patients Receiving Intravenous Thrombolysis Chih-Hao Chen, Sung-Chun Tang, [...], Jiann-Shing Jeng Changes in Bacterial and Fungal Communities across Compost Recipes, Preparation Methods, and Composting Times Deborah A. Neher, Thomas R. Weicht, [...], Noah Fierer Activation of Olfactory Receptors on Mouse Pulmonary Gene Expression, Single Nucleotide Variant and Fusion Transcript Macrophages Promotes Monocyte Chemotactic Protein-1 Production Discovery in Archival Material from Breast Tumors Jing Jing Li, Hock L. Tay, [...], Ming Yang Nadine Norton, Zhifu Sun, [...], E. Aubrey Thompson HDAC4 Does Not Act as a Protein Deacetylase in the Postnatal Murine Brain In Vivo Michal Mielcarek, Tamara Seredenina, [...], Gillian P. Bates Association between Telomere Length and Type 2 Diabetes Mellitus: A Meta-Analysis Jinzhao Zhao, Kun Miao, [...], Dao Wen Wang The USP21 Short Variant (USP21SV) Lacking NES, Located Mostly in the Nucleus In Vivo, Activates Transcription... Hiroshi Okuda, Hideki Ohdan, [...], Takashi Ito Neuronal Synapse Formation Induced by Microglia and Interleukin 10 So-Hee Lim, Eunha Park, [...], Jae-Ran Lee Cortical Reorganization after Hand Immobilization: The beta qEEG Spectral Coherence Evidences Marina Fortuna, Silmar Teixeira, [...], Oscar Arias-Carrión Improved Coomassie Blue Dye-Based Fast Staining Protocol for Proteins Separated by SDS-PAGE Pavel Májek, Zuzana Riedelová-Reicheltová, [...], Jan E. Dyr Journal of Immunology BRIEF REVIEWS Exploiting Apoptosis for Therapeutic Tolerance Induction Daniel R. Getts, Derrick P. McCarthy, and Stephen D. Miller J Immunol 2013 191:5341-5346; doi:10.4049/jimmunol.1302070 CUTTING EDGE Cutting Edge: IL-25 Elicits Innate Lymphoid Type 2 and Type II NKT Cells That Regulate Obesity in Mice Emily Hams, Richard M. Locksley, Andrew N. J. McKenzie, and Padraic G. Fallon J Immunol 2013 191:5349-5353; published ahead of print October 28, 2013,doi:10.4049/jimmunol.1301176 A Novel Approach to Tracking Antigen-Experienced CD4 T Cells into Functional Compartments via Tandem Deep and Shallow TCR Clonotyping Megan Estorninho, Vivienne B. Gibson, Deborah KronenbergVersteeg, Yuk-Fun Liu, Chester Ni, Karen Cerosaletti, and Mark Peakman J Immunol 2013 191:5430-5440; published ahead of print October 25, 2013,doi:10.4049/jimmunol.1300622 Posttranscriptional Gene Regulation of IL-17 by the RNABinding Protein HuR Is Required for Initiation of Experimental Autoimmune Encephalomyelitis Jing Chen, Jason Cascio, Joseph D. Magee, Patsharaporn Techasintana, Matthew M. Gubin, Garrett M. Dahm, Robert Calaluce, Shiguang Yu, and Ulus Atasoy J Immunol 2013 191:5441-5450; published ahead of Cutting Edge: Feed-Forward Activation of Phospholipase Cγ2 print October 28, 2013,doi:10.4049/jimmunol.1301188 via C2 Domain–Mediated Binding to SLP65 Michael Engelke, Thomas Oellerich, Kai Dittmann, He-Hsuan Hsiao, Acute-Phase Protein Hemopexin Is a Negative Regulator of Henning Urlaub, Hubert Serve, Christian Griesinger, and Jürgen Th17 Response and Experimental Autoimmune Wienands Encephalomyelitis Development J Immunol 2013 191:5354-5358; published ahead of print October Simona Rolla, Giada Ingoglia, Valentina Bardina, Lorenzo 28, 2013,doi:10.4049/jimmunol.1301326 Silengo, Fiorella Altruda, Francesco Novelli, and Emanuela Tolosano AUTOIMMUNITY J Immunol 2013 191:5451-5459; published ahead of print October 23, 2013,doi:10.4049/jimmunol.1203076 TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of Chronic Follicular Bronchiolitis Requires Antigen-Specific TL1A in Humoral Immune Responses Regulatory T Cell Control To Prevent Fatal Disease Xuehai Wang, Yan Hu, Tania Charpentier, Alain Lamarre, Shijie Progression Qi, Jiangping Wu, and Hongyu Luo Erica G. Schmitt, Dipica Haribhai, Jonathan C. Jeschke, Dominic J Immunol 2013 191:5420-5429; published ahead of print October O. Co, Jennifer Ziegelbauer, Ke Yan, Yoichiro Iwakura, Manoj K. 18, 2013,doi:10.4049/jimmunol.1301475 Mishra, Pippa Simpson, Nita H. Salzman, and Calvin B. Williams J Immunol 2013 191:5460-5476; published ahead of print October 25, 2013,doi:10.4049/jimmunol.1301576 Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis Martina Gatzka, Adelheid Hainzl, Thorsten Peters, Kamayani Singh, Alpaslan Tasdogan, Meinhard Wlaschek, and Karin Scharffetter-Kochanek J Immunol 2013 191:5477-5488; published ahead of print November 4, 2013,doi:10.4049/jimmunol.1300976 Regulatory T Cells Suppress the Late Phase of the Immune Response in Lymph Nodes through P-Selectin Glycoprotein Ligand-1 Stefano Angiari, Barbara Rossi, Laura Piccio, Bernd H. Zinselmeyer, Simona Budui, Elena Zenaro, Vittorina Della Bianca, Simone D. Bach, Elio Scarpini, Matteo BolominiVittori, Gennj Piacentino, Silvia Dusi, Carlo Laudanna, Anne H. Cross, Mark J. Miller, and Gabriela Constantin J Immunol 2013 191:5489-5500; published ahead of print October 30, 2013,doi:10.4049/jimmunol.1301235 IMMUNE REGULATION Unique Features of Naive CD8+ T Cell Activation by IL-2 Jae-Ho Cho, Hee-Ok Kim, Kyu-Sik Kim, Deok-Hwan Yang, Charles D. Surh, and Jonathan Sprent J Immunol 2013 191:5559-5573; published ahead of print October 28, 2013,doi:10.4049/jimmunol.1302293 Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells Sven Burghardt, Annette Erhardt, Benjamin Claass, Samuel Huber, Guido Adler, Thomas Jacobs, Athena Chalaris, Dirk Schmidt-Arras, Stefan Rose-John, Khalil Karimi, and Gisa Tiegs J Immunol 2013 191:5574-5582; published ahead of print October 18, 2013,doi:10.4049/jimmunol.1300826 Enhancing T Lineage Production in Aged Mice: A Novel Function of Foxn1 in the Bone Marrow Niche Erin C. Zook, Shubin Zhang, Rachel M. Gerstein, Pamela L. Witte, and Phong T. Le J Immunol 2013 191:5583-5593; published ahead of print November 1, 2013,doi:10.4049/jimmunol.1202278 Microglial Activation Milieu Controls Regulatory T Cell Responses Friederike Ebner, Christine Brandt, Peggy Thiele, Daniel Richter, Ulrike Schliesser, Volker Siffrin, Jutta Schueler, Tobias Stubbe, Agnes Ellinghaus, Christian Meisel, Birgit Sawitzki, and Robert Nitsch J Immunol 2013 191:5594-5602; published ahead of print October 21, 2013,doi:10.4049/jimmunol.1203331 INNATE IMMUNITY AND INFLAMMATION The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes Jillian Stephen, Barry Emerson, Keith A. A. Fox, and Ian Dransfield J Immunol 2013 191:5677-5683; published ahead of print October 16, 2013,doi:10.4049/jimmunol.1301250 CX3CR1 Regulates the Maintenance of KLRG1+ NK Cells into the Bone Marrow by Promoting Their Entry into Circulation Andrea Ponzetta, Giuseppe Sciumè, Giorgia Benigni, Fabrizio Antonangeli, Stefania Morrone, Angela Santoni, and Giovanni Bernardini J Immunol 2013 191:5684-5694; published ahead of print November 1, 2013,doi:10.4049/jimmunol.1300090 Tissue LyC6− Macrophages Are Generated in the Absence of Circulating LyC6− Monocytes and Nur77 in a Model of Muscle Regeneration Tamas Varga, Rémi Mounier, Peter Gogolak, Szilard Poliska, Bénédicte Chazaud, and Laszlo Nagy J Immunol 2013 191:5695-5701; published ahead of print October 16, 2013,doi:10.4049/jimmunol.1301445 Regulation of Apoptosis and Innate Immune Stimuli in Inflammation-Induced Preterm Labor Mukesh K. Jaiswal, Varkha Agrawal, Timothy Mallers, Alice Gilman-Sachs, Emmet Hirsch, and Kenneth D. Beaman J Immunol 2013 191:5702-5713; published ahead of print October 25, 2013,doi:10.4049/jimmunol.1301604 p33 (gC1q Receptor) Prevents Cell Damage by Blocking the Cytolytic Activity of Antimicrobial Peptides Johannes Westman, Finja C. Hansen, Anders I. Olin, Matthias Mörgelin, Artur Schmidtchen, and Heiko Herwald J Immunol 2013 191:5714-5721; published ahead of print October 30, 2013,doi:10.4049/jimmunol.1300596 Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands Emily McFall, Megan M. Tu, Nuha Al-Khattabi, Lee-Hwa Tai, Aaron S. St.-Laurent, Velina Tzankova, Clayton W. Hall, Simon Belanger, Angela D. Troke, Andrew Wight, Ahmad Bakur Mahmoud, Haggag S. Zein, Mir Munir A. Rahim, James R. Carlyle, and Andrew P. Makrigiannis J Immunol 2013 191:5722-5729; published ahead of print October 23, 2013,doi:10.4049/jimmunol.1300726 Exploiting Apoptosis for Therapeutic Tolerance Induction Daniel R. Getts1, Derrick P. McCarthy1 and Stephen D. Miller +Author Affiliations Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 ↵1 D.R.G. and D.P.M. contributed equally. Immune tolerance remains the most promising yet elusive strategy for treating immune-mediated diseases. An experimental strategy showing promise in phase 1 clinical studies is the delivery of Ag cross-linked to apoptotic leukocytes using ethylene carbodiimide. This approach originated from demonstration of the profound tolerance-inducing ability of i.v. administered Ag-coupled splenocytes (Ag-SP) in mice, which has been demonstrated to treat T cell–mediated disorders including autoimmunity, allergy, and transplant rejection. Recent studies have defined the intricate interplay between the innate and adaptive immune systems in Ag-SP tolerance induction. Innate mechanisms include scavenger receptor–mediated uptake of Ag-SP by host APCs, Ag representation, and the required upregulation of PD-L1 expression and IL-10 production by splenic marginal zone macrophages leading to Ag-specific T cell regulation via the combined effects of cellintrinsic anergy and regulatory T cell induction. In this paper, we discuss the history, advantages, current mechanistic understanding, and clinical potential of tolerance induction using apoptotic Agcoupled apoptotic leukocytes. Exosomes Secreted by Human Placenta Carry Functional Fas Ligand and TRAIL Molecules and Convey Apoptosis in Activated Immune Cells, Suggesting Exosome-Mediated Immune Privilege of the Fetus Ann-Christin Stenqvist, Olga Nagaeva, Vladimir Baranov and Lucia Mincheva-Nilsson +Author Affiliations Division of Clinical Immunology, Department of Clinical Microbiology, Umeå University, S-90185 Umeå, Sweden Apoptosis is crucially important in mediating immune privilege of the fetus during pregnancy. We investigated the expression and in vitro apoptotic activity of two physiologically relevant death messengers, the TNF family members Fas ligand (FasL) and TRAIL in human early and term placentas. Both molecules were intracellularly expressed, confined to the late endosomal compartment of the syncytiotrophoblast, and tightly associated to the generation and secretion of placental exosomes. Using immunoelectron microscopy, we show that FasL and TRAIL are expressed on the limiting membrane of multivesicular bodies where, by membrane invagination, intraluminal microvesicles carrying membranal bioactive FasL and TRAIL are formed and released in the extracellular space as exosomes. Analyzing exosomes secreted from placental explant cultures, to our knowledge, we demonstrate for the first time that FasL and TRAIL are clustered on the exosomal membrane as oligomerized aggregates ready to form death-inducing signaling complex. Consistently, placental FasL- and TRAIL-carrying exosomes triggered apoptosis in Jurkat T cells and activated PBMC in a dose-dependent manner. Limiting the expression of functional FasL and TRAIL to exosomes comprise a dual benefit: 1) storage of exosomal FasL and TRAIL in multivesicular bodies is protected from proteolytic cleavage and 2) upon secretion, delivery of preformed membranal death molecules by exosomes rapidly triggers apoptosis. Our results suggest that bioactive FasL- and TRAIL-carrying exosomes, able to convey apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its exosome-secreting ability. Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells Sven Burghardt*, Annette Erhardt*, Benjamin Claass*, Samuel Huber†, Guido Adler‡, Thomas Jacobs‡, Athena Chalaris§, Dirk Schmidt-Arras§, Stefan Rose-John§, Khalil Karimi* and Gisa Tiegs* +Author Affiliations *Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg–Eppendorf, 20246 Hamburg, Germany; †Medical Clinic, University Medical Center Hamburg–Eppendorf, 20246 Hamburg, Germany; ‡Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, 20259 Hamburg, Germany; and §Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany The “liver tolerance effect” has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10– dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A. In this study, we show that HCs, particularly those from regenerating livers of Con A–pretreated mice, induced a regulatory phenotype in naive CD4+ T cells in vitro. Using reporter mice, we observed that these T regulatory cells released substantial amounts of IL-10, produced IFN-γ, failed to express Foxp3, but suppressed proliferation of responder T cells upon restimulation with anti-CD3 mAb. Hence, these regulatory cells feature a similar phenotype as the recently described IL-10– producing Th1 cells, which are generated upon activation of Notch signaling. Indeed, inhibition of γsecretase and a disintegrin and metalloproteinase 17 but not a disintegrin and metalloproteinase 10, respectively, which blocked Notch activation, prevented IL-10 secretion. HCs from Con A– pretreated mice showed enhanced expression of the Notch ligand Jagged1 and significantly increased receptor density of Notch1 on CD4+ T cells. However, HCs from Con A–pretreated IFN regulatory factor 1−/− mice, which cannot respond to IFN-γ, as well as those from IFN-γ−/− mice failed to augment IL-10 production by CD4+ T cells. In conclusion, it seems that HCs fine-tune liver inflammation by upregulation of Jagged1 and activation of Notch signaling in Th1 cells. This mechanism might be of particular importance in the regenerating liver subsequent to Th1-mediated hepatitis.