Transcript [Science] 22 NOVEMBER 2013 VOL 342, ISSUE 6161, PAGES 901

[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.