Transcript [Science] 5 JULY 2013 VOL 341, ISSUE 6141, PAGES 1-100

[Science] 12 JULY 2013 VOL 341, ISSUE 6142, PAGES 101-208
Perspectives - CANCER
Prostate Cancer Takes Nerve
John T. Isaacs
Science 12 July 2013: 134-135.
Prostate cancer development and metastasis is driven by invasion of the tumor by the
nervous system.
Science. 2013 Jul 12;341(6142):1236361.
Autonomic Nerve Development Contributes to Prostate Cancer Progressi
on.
Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS.
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein
College of Medicine, Bronx, NY 10461, USA.
Nerves are a common feature of the microenvironment, but their role in tumor growth
and progression remains unclear. We found that the formation of autonomic nerve fibers
in the prostate gland regulates prostate cancer development and dissemination in mouse
models. The early phases of tumor development were prevented by chemical or surgical
sympathectomy and by genetic deletion of stromal β2- and β3-adrenergic receptors.
Tumors were also infiltrated by parasympathetic cholinergic fibers that
promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis were
inhibited by pharmacological blockade or genetic disruption of the stromal type 1
muscarinic receptor, leading to improved survival of the mice. A retrospective blinded
analysis of prostate adenocarcinoma specimens from 43 patients revealed that the
densities of sympathetic and parasympathetic nerve fibers in tumor and surrounding
normal tissue, respectively, were associated with poor clinical outcomes. These findings
may lead to novel therapeutic approaches for prostate cancer.
Tumor innervation.
Prostate cancer is initiated by sympathetic nerves that release norepinephrine (NE),
which activates adrenergic receptors (Adrβ2, Adrβ3) on stromal cells.
Parasympathetic nerves release acetylcholine (ACh), which acts on type 1 muscarinic
receptors on stromal cells, promoting cancer cell proliferation
and metastasis.
[Science] 12 JULY 2013 VOL 341, ISSUE 6142, PAGES 101-208
Perspectives - GENETICS
Moving Beyond “Isolated” Gene Patents
Science 12 July 2013: 137-138.
The U.S. Supreme Court decides that not all gene patents are alike—what does this mean for research, innovation, business,
and patients?
Reports
Structural Basis for the Counter-Transport Mechanism of a H+/Ca2+ Exchanger
Science 12 July 2013: 168-172.
Membrane proteins that exchange calcium ions for cations regulate access by sliding their helices around the ions.
Crystal Structure of NLRC4 Reveals Its Autoinhibition Mechanism
Science 12 July 2013: 172-175.
Adenosine diphosphate binding to the NOD-like receptor keeps it inactive in the absence of ligands.
Biosynthesis of Antinutritional Alkaloids in Solanaceous Crops Is Mediated by Clustered Genes
Science 12 July 2013: 175-179.
Some of the chemicals that domestication has reduced in potato and tomato are derived from clusters of biosynthetic
genes.
Genome-Wide Comparison of Medieval and Modern Mycobacterium leprae
Science 12 July 2013: 179-183.
Five European individuals who lived during the Middle Ages provide a look backward at leprosy.
Infectivity, Transmission, and Pathology of Human-Isolated H7N9 Influenza Virus in Ferrets and Pigs
Science 12 July 2013: 183-186.
An emergent avian influenza virus shows high contact transmissibility but limited capacity for airborne spread between
mammals.
Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D
Science 12 July 2013: 186-191.
Magnesium supplementation in patients with a primary immunodeficiency restores immune responses to Epstein-Barr virus.
Microcircuits for Hierarchical Elaboration of Object Coding Across Primate Temporal Areas
Science 12 July 2013: 191-195.
Neuronal activity representing novel features emerges in hierarchically lower brain areas earlier than previously thought.
[Science] 5 JULY 2013 VOL 341, ISSUE 6141, PAGES 1-100
Perspectives – IMMUNOLOGY
Making Macrophages Eat Cancer
Antibody-based therapies to treat cancer may get a boost from an adjuvant that prevents cancer cells from escaping
engulfment by macrophages.
Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.
Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified
the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity
SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity
SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their
own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonalantibodies tested by increasing
phagocytosis in vitro and enhancing antitumor responses in vivo. This "one-two punch" directs immune responses against
tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting
the efficacy of therapeutic anticancer antibodies.
[Science] 5 JULY 2013 VOL 341, ISSUE 6141, PAGES 1-100
Science. 2013 Jul 5;341(6141):1237439. doi: 10.1126/science.1237439.
The long-term stability of the human gut microbiota.
Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, Clemente JC, Knight R, Heath AC, Leibel RL, Rosenbaum M, Gordon JI.
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
A low-error 16S ribosomal RNA amplicon sequencing method, in combination with whole-genome sequencing of >500
cultured isolates, was used to characterize bacterial strain composition in the fecal microbiota of 37 U.S. adults sampled for
up to 5 years. Microbiota stability followed a power-law function, which when extrapolated suggests that most strains in an
individual are residents for decades. Shared strains were recovered from family members but not from unrelated individuals.
Sampling of individuals who consumed a monotonous liquid diet for up to 32 weeks indicated that changes in strain
composition were better predicted by changes in weight than by differences in sampling interval. This combination
of stability and responsiveness to physiologic change confirms the potential of the gut microbiota as a diagnostic tool and
therapeutic target.
MiR-200b and miR-429 Function in Mouse Ovulation and Are Essential for Female Fertility
Science 5 July 2013: 71-73.
MicroRNAs regulate hormone synthesis in the pituitary and the production of oocytes.
A Secreted Disulfide Catalyst Controls Extracellular Matrix Composition and Function
Science 5 July 2013: 74-76.
Laminin incorporation is promoted by a secreted enzyme, which is important for cell adhesion and migration.
Structure of the Repulsive Guidance Molecule (RGM)–Neogenin Signaling Hub
Science 5 July 2013: 77-80.
A complex of a guidance molecule and its receptor reveals how signals cross the membrane.
Inhibition of RNA Helicase Brr2 by the C-Terminal Tail of the Spliceosomal Protein Prp8
Science 5 July 2013: 80-84.
Regulating an RNA helicase in the eukaryotic splicing reaction involves intermittent blockade of the catalytic tunnel.
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Science 5 July 2013: 84-87.
A method to monitor drug binding to proteins in cells may help in target validation and drug optimization.
[Science Sig] 9 JULY 2013 VOL 6, ISSUE 283
Sci Signal. 2013 Jul 9;6(283):ra55. doi: 10.1126/scisignal.2003900.
Blockade of Glioma Proliferation Through Allosteric Inhibition of JAK2.
He K, Qi Q, Chan CB, Xiao G, Liu X, Tucker-Burden C, Wang L, Mao H, Lu X, McDonald FE, Luo H, Fan QW, Weiss WA, Sun SY, Brat DJ, Ye K.
1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human
cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies
in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has
been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase
2 (JAK2)-mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by
binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and
inducing cell cycle arrest. G5-7 inhibited the proliferation of PTEN-deficient glioblastoma cell lines harboring a
constitutively active variant of EGFR (U87MG/EGFRvIII) and human glioblastoma explant neurosphere cultures, but the drug
only weakly inhibited the proliferation of either glioblastoma cell lines that were wild type for EGFR and stably transfected
with PTEN (U87MG/PTEN) or normal neural progenitor cells and astrocytes. Additionally, G5-7 reduced vascular endothelial
growth factor (VEGF) secretion and endothelial cell migration and induced apoptosis in glioblastoma xenografts, thereby
suppressing glioblastoma growth in vivo. Furthermore, G5-7 was more potent than EGFR or JAK2 inhibitors that interfere
with either ligand or adenosine 5'-triphosphate (ATP) binding at impeding glioblastoma cell proliferation, demonstrating
that this allosteric JAK2 inhibitor may be an effective clinical strategy.
[Science Sig] 9 JULY 2013 VOL 6, ISSUE 283
Computational Biology
Regulators of Calcium Homeostasis Identified by Inference of Kinetic Model Parameters from Live Single Cells
Perturbed by siRNA
Estimation of parameters in a calcium regulatory network from single-cell data illustrates how this approach can reveal
protein function.
Neuroscience
JNK3 Couples the Neuronal Stress Response to Inhibition of Secretory Trafficking
Palmitoylated JNK3 sequesters the phosphatase Sac1 at the Golgi to limit trafficking of glutamate receptors to the cell
surface.
[Science Sig] 2 JULY 2013 VOL 6, ISSUE 282
Receptor-Ligand Interactions
The Basis for the Distinct Biological Activities of Vascular Endothelial Growth Factor Receptor–1 Ligands
Differences in how two ligands interact with VEGFR-1 explain why only one ligand is strongly angiogenic.
Cancer
Estrogen Alters the Splicing of Type 1 Corticotropin-Releasing Hormone Receptor in Breast Cancer Cells
Altered splicing of a stress hormone receptor correlates with estrogen receptor–positive breast cancer.
Biochemistry
A Kinetic Test Characterizes Kinase Intramolecular and Intermolecular Autophosphorylation Mechanisms
Mathematical analysis of enzyme kinetics reveals different modes of kinase autophosphorylation.
[Science Trans Med] 10 JULY 2013 VOL 5, ISSUE 193
BONE
Vitamin D Deficiency Induces Early Signs of Aging in Human Bone, Increasing the Risk of Fracture
In addition to decreasing bone mass, vitamin D deficiency causes early aging of the remaining mineralized bone and leads
to severe losses in fracture resistance.
IMMUNE THROMBOCYTOPENIC PURPURA
Plasmacytoid Dendritic Cells, Interferon Signaling, and FcγR Contribute to Pathogenesis and Therapeutic Response in
Childhood Immune Thrombocytopenia
Targeting plasmacytoid dendritic cells or blockade of interferon response may benefit patients with an autoimmune disease
against platelets.
INTRACRANIAL HEMORRHAGE
Overexpression of Vascular Endothelial Growth Factor in the Germinal Matrix Induces Neurovascular Proteases and
Intraventricular Hemorrhage
A transgenic mouse model implicates specific neurovascular proteases in the pathogenesis of intracranial hemorrhage in
preterm infants.
HIV
Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism
Gut-resident microbial populations may influence intestinal homeostasis during HIV disease.
[Science Trans Med] 3 JULY 2013 VOL 5, ISSUE 192
ANTIBIOTICS
Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells
Mitochondrial dysfunction and oxidative damage induced by bactericidal antibiotics in mammalian cells may be alleviated
by an antioxidant or prevented by preferential use of bacteriostatic antibiotics.
GENOMICS
Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta
Natural selection in a Bangladeshi population from the cholera-endemic Ganges River Delta has targeted genes associated
with cholera resistance and an innate immunity pathway activated by Vibrio cholerae.
IMMUNOLOGY
TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer
A Streptamer-based koff rate assay identifies T cells with high protective capacity for the adoptive transfer.
Threshold-controlled ubiquitination of the EGFR directs receptor fate
Sara Sigismund1, Veronica Algisi1, Gilda Nappo1, Alexia Conte1, Roberta Pascolutti1, Alessandro Cuomo2, Tiziana Bonaldi2,
Elisabetta Argenzio1,4, Lisette G G C Verhoef1, Elena Maspero1, Fabrizio Bianchi2, Fabrizio Capuani1,5, Andrea Ciliberto1,
Simona Polo1,3 and Pier Paolo Di Fiore1,2,3
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy
Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
Correspondence to:
Pier Paolo Di Fiore, Department of Experimental Oncology, IEO-European Institute of Oncology, Via Adamello 16, 20139
Milan, Italy. Tel.:+39 02 574303247; Fax:+39 02 574303231; E-mail: [email protected]
or Simona Polo, Department of Experimental Oncology, IEO-European Institute of Oncology, Via Adamello 16, 20139
Milan, Italy. Tel.:+39 02 574303242; Fax:+39 02 574303231; E-mail: [email protected]
4Present address: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
5Present address: Dipartimento di Fisica, Università di Roma La Sapienza, Rome, Italy.
Received 4 January 2013; Accepted 3 June 2013
How the cell converts graded signals into threshold-activated responses is a question of
great biological relevance. Here, we uncover a nonlinear modality of epidermal growth
factor receptor (EGFR)-activated signal transduction, by demonstrating that the
ubiquitination of the EGFR at the PM is threshold controlled. The ubiquitination threshold
is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in
complex with Grb2, to the EGFR. This, in turn, is dependent on the simultaneous presence
of two phosphotyrosines, pY1045 and either one of pY1068 or pY1086, on the same EGFR
moiety. The dose–response curve of EGFR ubiquitination correlate precisely with the nonclathrin endocytosis (NCE) mode of EGFR internalization. Finally, EGFR-NCE mechanistically
depends on EGFR ubiquitination, as the two events can be simultaneously re-engineered
on a phosphorylation/ubiquitination-incompetent EGFR backbone. Since NCE controls the
degradation of the EGFR, our findings have implications for how the cell responds to
increasing levels of EGFR signalling, by varying the balance of receptor signalling and
degradation/attenuation.
Functional determinants of the quorum-sensing non-coding RNAs and their roles
in target regulation
Yi Shao1,3, Lihui Feng1,3, Steven T Rutherford1, Kai Papenfort1 and Bonnie L Bassler1,2
Department of Molecular Biology, Princeton University, Princeton, NJ, USA
Howard Hughes Medical Institute, Chevy Chase, MD, USA
Correspondence to:
Bonnie L Bassler, Department of Molecular Biology, Princeton University, 329 Lewis Thomas Labs, Princeton, NJ 08544, USA.
Tel.:+1 609 258 2857; Fax:+1 609 258 2957; E-mail: [email protected]
3These authors contributed equally to this work.
Received 3 April 2013; Accepted 4 June 2013
Quorum sensing is a chemical communication process that bacteria use to control collective
behaviours including bioluminescence, biofilm formation, and virulence factor production. In
Vibrio harveyi, five homologous small RNAs (sRNAs) called Qrr1–5, control quorum-sensing
transitions. Here, we identify 16 new targets of the Qrr sRNAs. Mutagenesis reveals that
particular sequence differences among the Qrr sRNAs determine their target specificities.
Modelling coupled with biochemical and genetic analyses show that all five of the Qrr sRNAs
possess four stem-loops: the first stem-loop is crucial for base pairing with a subset of targets.
This stem-loop also protects the Qrr sRNAs from RNase E-mediated degradation. The second
stem-loop contains conserved sequences required for base pairing with the majority of the
target mRNAs. The third stem-loop plays an accessory role in base pairing and stability. The
fourth stem-loop functions as a rho-independent terminator. In the quorum-sensing regulon,
Qrr sRNAs-controlled genes are the most rapid to respond to quorum-sensing autoinducers.
The Qrr sRNAs are conserved throughout vibrios, thus insights from this work could apply
generally to Vibrio quorum sensing.
•12 JULY 2013
•25 JUNE 2013
•Compact Parkin only: insights into the structure of an autoinhibited
ubiquitin ligase FREE
•DNA polymerase κ-dependent DNA synthesis at stalled replication forks
is important for CHK1 activation EMBO OPEN
FIVE RECENT STUDIES PROVIDE LONG-AWAITED STRUCTURAL VIEWS OF THE INTRICATE
INTERDOMAIN ARRANGEMENTS THAT CONTROL HYBRID RBR FAMILY UBIQUITIN
LIGASES.
R ANDREW BYRD AND ALLAN M WEISSMAN
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 12 JULY 2013;
DOI:10.1038/EMBOJ.2013.158
•09 JULY 2013
•Functional determinants of the quorum-sensing non-coding RNAs and
their roles in target regulation EMBO OPEN
QUORUM SENSING IN BACTERIA IS CONTROLLED BY FIVE SMALL RNAS, QRR1–5, WHICH
EXERT POST-TRANSCRIPTIONAL CONTROL OF 16 NOVEL TARGET GENES THROUGH
FOUR CONSERVED STEM-LOOPS WITH DISTINCT ROLES IN TARGET BINDING AND SRNA
STABILITY.
YI SHAO, LIHUI FENG, STEVEN T RUTHERFORD, KAI PAPENFORT AND BONNIE L BASSLER
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 09 JULY 2013;
DOI:10.1038/EMBOJ.2013.155
•05 JULY 2013
•Histone deacetylases govern heterochromatin in every phase FREE
SIR2-DEPENDENT HISTONE DEACETYLATION RECRUITS THE HISTONE
METHYLTRANSFERASE CLR4, SPREADING REPRESSIVE H3K9-METHYLATION DURING
CENTROMERIC HETEROCHROMATIN ASSEMBLY.
YOTA MURAKAMI
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 05 JULY 2013;
DOI:10.1038/EMBOJ.2013.154
•28 JUNE 2013
•KIF16B delivers for transcytosis FREE
EPITHELIA THAT NATIVELY LACK THE CLATHRIN ADAPTOR AP-1B RECYCLE
BASOLATERAL PROTEINS TO THEIR APICAL DOMAIN BY TRANSCYTOSIS. ALTHOUGH
MICROTUBULES ARE REQUIRED FOR THIS PROCESS, KIF16B IS THE FIRST KINESIN
IDENTIFIED TO BE INVOLVED IN TRANSCYTOSIS.
ALEJO E RODRÍGUEZ-FRATICELLI, MANUEL GALVEZ-SANTISTEBAN AND FERNANDO
MARTIN-BELMONTE
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 28 JUNE 2013;
DOI:10.1038/EMBOJ.2013.153
Ral mediates activity-dependent growth of postsynaptic membranes via
recruitment of the exocyst
POSTSYNAPTIC MEMBRANE REMODELLING REQUIRES VESICLE TRAFFICKING. THE
SMALL GTPASE RAL IS ACTIVATED IN RESPONSE TO CALCIUM INFLUX AND REGULATES
THE EXOCYST COMPLEX, THEREFORE PROVIDING A LINK BETWEEN SYNAPTIC ACTIVITY
AND MEMBRANE TRAFFICKING.
RITA O TEODORO, GULÇIN PEKKURNAZ, ABDULLAH NASSER, MISAO E HIGASHIKOVTUN, MARIA BALAKIREVA, IAN G MCLACHLAN, JACQUES CAMONIS AND THOMAS L
SCHWARZ
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 28 JUNE 2013;
DOI:10.1038/EMBOJ.2013.147
A VERTEBRATE TRANSLESION SYNTHESIS DNA POLYMERASE BROADLY CONTRIBUTES
TO CHECKPOINT-ACTIVATING PRIMER SYNTHESIS AT STALLED REPLICATION FORKS, A
ROLE PREVIOUSLY ASCRIBED ONLY TO REPLICATIVE POLYMERASES.
RÉMY BÉTOUS, MARIE-JEANNE PILLAIRE, LAURA PIERINI, SIEM VAN DER LAAN,
BÉNÉDICTE RECOLIN, EMMA OHL-SÉGUY, CAIXIA GUO, NAOKO NIIMI, PETR GRÚZ,
TAKEHIKO NOHMI, ERROL FRIEDBERG, CHRISTOPHE CAZAUX, DOMENICO MAIORANO
AND JEAN-SÉBASTIEN HOFFMANN
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 25 JUNE 2013;
DOI:10.1038/EMBOJ.2013.148
•Threshold-controlled ubiquitination of the EGFR directs receptor
fate EMBO OPEN
THE AMOUNT OF EGF PRESENT FOR BINDING TO ITS RECEPTOR GOVERNS AN ON–OFF
SWITCH OF EGFR UBIQUITINATION AND HENCE LIGAND-CONTROLLED NON-CLATHRINMEDIATED ENDOCYTOSIS AND EGFR DEGRADATION.
SARA SIGISMUND, VERONICA ALGISI, GILDA NAPPO, ALEXIA CONTE, ROBERTA
PASCOLUTTI, ALESSANDRO CUOMO, TIZIANA BONALDI, ELISABETTA ARGENZIO, LISETTE
G G C VERHOEF, ELENA MASPERO, FABRIZIO BIANCHI, FABRIZIO CAPUANI, ANDREA
CILIBERTO, SIMONA POLO AND PIER PAOLO DI FIORE
THE EMBO JOURNAL ADVANCE ONLINE PUBLICATION 25 JUNE 2013;
DOI:10.1038/EMBOJ.2013.149
BRIEF REVIEWS
Immune Regulation in Obesity-Associated Adipose
Inflammation
Jonathan M. Han and
Megan K. Levings
J Immunol 2013 191:527-532; doi:10.4049/jimmunol.1301035
CUTTING EDGE
Cutting Edge: ABIN-1 Protects against Psoriasis by
Restricting MyD88 Signals in Dendritic Cells
Joseph A. Callahan, Gianna E. Hammer, Alexander Agelides, Bao
H. Duong, Shigeru Oshima, Jeffrey North, Rommel Advincula,
Nataliya Shifrin, Hong-An Truong, Jonathan Paw, Julio Barrera,
Anthony DeFranco, Michael D. Rosenblum, Barbara A. Malynn,
and Averil Ma
J Immunol 2013 191:535-539; published ahead of print June 19,
2013, doi:10.4049/jimmunol.1203335
Cutting Edge: Prolonged Exposure to HIV Reinforces a
Poised Epigenetic Program for PD-1 Expression in VirusSpecific CD8 T Cells
Ben Youngblood, Alessandra Noto, Filippos Porichis, Rama S.
Akondy, Zaza M. Ndhlovu, James W. Austin, Rebeka Bordi,
Francesco A. Procopio, Toshiyuki Miura, Todd M. Allen, John
Sidney, Alessandro Sette, Bruce D. Walker, Rafi Ahmed, Jeremy
M. Boss, Rafick-Pierre Sékaly, and Daniel E. Kaufmann
J Immunol 2013 191:540-544; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1203161
Cutting Edge: Conditional MHC Class II Expression
Reveals a Limited Role for B Cell Antigen Presentation in
Primary and Secondary CD4 T Cell Responses
Angela S. Archambault, Javier A. Carrero, Lisa G. Barnett, Nigel
G. McGee, Julia Sim, Jonathan O. Wright, Tobias Raabe,
Peiquin Chen, Hua Ding, Eric J. Allenspach, Ioannis Dragatsis,
Terri M. Laufer, and Gregory F. Wu
J Immunol 2013 191:545-550; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1201598
AUTOIMMUNITY
Different Modulation of Ptpn22 in Effector and Regulatory T
Cells Leads to Attenuation of Autoimmune Diabetes in
Transgenic Nonobese Diabetic Mice
Li-Tzu Yeh, Shi-Chuen Miaw, Ming-Hong Lin, Feng-Cheng Chou,
Shing-Jia Shieh, Yi-Ping Chuang, Shih-Hua Lin, Deh-Ming
Chang, and Huey-Kang Sytwu
J Immunol 2013 191:594-607; published ahead of print June 10,
2013, doi:10.4049/jimmunol.1203380
Different Stages of Primary Sjögren’s Syndrome Involving
Lymphotoxin and Type 1 IFN
Long Shen, Lakshmanan Suresh, Kishore Malyavantham,
Przemek Kowal, Jingxiu Xuan, Matthew J. Lindemann, and
Julian L. Ambrus, Jr.
J Immunol 2013 191:608-613; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1203440
Systemic Lack of Canonical Histamine Receptor Signaling
Results in Increased Resistance to Autoimmune
Encephalomyelitis
Naresha Saligrama, Laure K. Case, Roxana del Rio, Rajkumar
Noubade, and Cory Teuscher
J Immunol 2013 191:614-622; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1203137
IMMUNE REGULATION
T Cell Activation Threshold Regulated by E3 Ubiquitin Ligase
Cbl-b Determines Fate of Inducible Regulatory T Cells
Guilin Qiao, Yixia Zhao, Zhenping Li, Peter Q. Tang, Wallace Y.
Langdon, Tianlan Yang, and Jian Zhang
J Immunol 2013 191:632-639; published ahead of print June 7,
2013, doi:10.4049/jimmunol.1202068
uR Is Required for IL-17–Induced Act1-Mediated CXCL1 and
CXCL5 mRNA Stabilization
Tomasz Herjan, Peng Yao, Wen Qian, Xiao Li, Caini Liu,
Katarzyna Bulek, Dongxu Sun, Wen-Pin Yang, Jun Zhu, Aiqing He,
Julie A. Carman, Serpil C. Erzurum, Howard D. Lipshitz, Paul L.
Fox, Thomas A. Hamilton, and Xiaoxia Li
J Immunol 2013 191:640-649; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1203315
Control of T Cell Fates and Immune Tolerance by p38α
Signaling in Mucosal CD103+ Dendritic Cells
Gonghua Huang, Yanyan Wang, and Hongbo Chi
J Immunol 2013 191:650-659; published ahead of print June 10,
2013, doi:10.4049/jimmunol.1300398
Human Bocavirus VP2 Upregulates IFN-β Pathway by
Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of
Retinoic Acid–Inducible Gene-I
Huanle Luo, Zhenfeng Zhang, Zhenhua Zheng, Xianliang Ke,
Xiaowei Zhang, Qian Li, Yan Liu, Bingke Bai, Panyong Mao,
Qinxue Hu, and Hanzhong Wang
J Immunol 2013 191:660-669; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1202933
IL-4 Upregulates Igα and Igβ Protein, Resulting in
Augmented IgM Maturation and B Cell Receptor–Triggered
B Cell Activation
Benchang Guo and Thomas L. Rothstein
J Immunol 2013 191:670-677; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1203211
STAT4 and T-bet Are Required for the Plasticity of IFN-γ
Expression across Th2 Ontogeny and Influence Changes in
Ifng Promoter DNA Methylation
Christopher L. Williams, Marcia M. Schilling, Sung Hoon Cho,
Keunwook Lee, Mei Wei, Aditi, and Mark Boothby
J Immunol 2013 191:678-687; published ahead of print June 12,
2013, doi:10.4049/jimmunol.1203360
Contrasting Effects of Anti-Ly49A Due to MHC Class I cis
Binding on NK Cell–Mediated Allogeneic Bone Marrow Cell
Resistance
Maite Alvarez, Can M. Sungur, Erik Ames, Stephen K. Anderson,
Claire Pomeroy, and William J. Murphy
J Immunol 2013 191:688-698; published ahead of print June 10,
2013, doi:10.4049/jimmunol.1300202
Critical Role of the Tumor Suppressor Tuberous Sclerosis
Complex 1 in Dendritic Cell Activation of CD4 T Cells by
Promoting MHC Class II Expression via IRF4 and CIITA
Hongjie Pan, Thomas F. O’Brien, Gabriela Wright, Jialong Yang,
Jinwook Shin, Kenneth L. Wright, and Xiao-Ping Zhong
J Immunol 2013 191:699-707; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1201443
RKIP Contributes to IFN-γ Synthesis by CD8+ T Cells after
Serial TCR Triggering in Systemic Inflammatory Response
Syndrome
Kyle T. Wright and Anthony T. Vella
J Immunol 2013 191:708-716; published ahead of print June 12,
2013, doi:10.4049/jimmunol.1203486
An Alternative Role for Foxp3 As an Effector T Cell Regulator
Controlled through CD40
Gisela M. Vaitaitis, Jessica R. Carter, Dan M. Waid, Michael H.
Olmstead, and David H. Wagner, Jr.
J Immunol 2013 191:717-725; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1300625
INFECTIOUS DISEASE AND HOST RESPONSE
Microenvironments in Tuberculous Granulomas Are
Delineated by Distinct Populations of Macrophage Subsets
and Expression of Nitric Oxide Synthase and Arginase
Isoforms
Joshua T. Mattila, Olabisi O. Ojo, Diane Kepka-Lenhart, Simeone
Marino, Jin Hee Kim, Seok Yong Eum, Laura E. Via, Clifton E.
Barry III, Edwin Klein, Denise E. Kirschner, Sidney M. Morris, Jr.,
Philana Ling Lin, and JoAnne L. Flynn
J Immunol 2013 191:773-784; published ahead of print June 7,
2013, doi:10.4049/jimmunol.1300113
Identification and Prioritization of Merozoite Antigens as
Targets of Protective Human Immunity to Plasmodium
falciparum Malaria for Vaccine and Biomarker Development
Jack S. Richards, Thangavelu U. Arumugam, Linda Reiling,
Julie Healer, Anthony N. Hodder, Freya J. I. Fowkes, Nadia
Cross, Christine Langer, Satoru Takeo, Alex D. Uboldi, Jennifer
K. Thompson, Paul R. Gilson, Ross L. Coppel, Peter M. Siba,
Christopher L. King, Motomi Torii, Chetan E. Chitnis, David L.
Narum, Ivo Mueller, Brendan S. Crabb, Alan F. Cowman,
Takafumi Tsuboi, and James G. Beeson
J Immunol 2013 191:795-809; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1300778
B Cell–Intrinsic TLR7 Signaling Is Required for Optimal B
Cell Responses during Chronic Viral Infection
Jonathan M. Clingan and Mehrdad Matloubian
J Immunol 2013 191:810-818; published ahead of print June 12,
2013, doi:10.4049/jimmunol.1300244
INNATE IMMUNITY AND INFLAMMATION
Erythrocyte-Binding Antigens of Plasmodium falciparum Are
Targets of Human Inhibitory Antibodies and Function To
Evade Naturally Acquired Immunity
Kristina E. M. Persson, Freya J. I. Fowkes, Fiona J. McCallum,
Nimmo Gicheru, Linda Reiling, Jack S. Richards, Danny W.
Wilson, Sash Lopaticki, Alan F. Cowman, Kevin Marsh, and
James G. Beeson
J Immunol 2013 191:785-794; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1300444
Combined Inhibition of Complement (C5) and CD14
Markedly Attenuates Inflammation, Thrombogenicity, and
Hemodynamic Changes in Porcine Sepsis
Andreas Barratt-Due, Ebbe B. Thorgersen, Kjetil Egge, Søren
Pischke, Andrey Sokolov, Bernt C. Hellerud, Julie K. Lindstad,
Anne Pharo, Anjan K. Bongoni, Robert Rieben, Miles Nunn,
Helge Scott, and Tom E. Mollnes
J Immunol 2013 191:819-827; published ahead of print June 12,
2013, doi:10.4049/jimmunol.1201909
CD160 Activation by Herpesvirus Entry Mediator Augments
Inflammatory Cytokine Production and Cytolytic Function by
NK Cells
John R. Šedý, Ryan L. Bjordahl, Vasileios Bekiaris, Matthew G.
Macauley, Brian C. Ware, Paula S. Norris, Nell S. Lurain, Chris A.
Benedict, and Carl F. Ware
J Immunol 2013 191:828-836; published ahead of print June 12,
2013, doi:10.4049/jimmunol.1300894
Trp53 Deficiency Protects against Acute Intestinal
Inflammation
Martina E. Spehlmann, Carolin F. Manthey, Sara M. Dann, Elaine
Hanson, Sukhman S. Sandhu, Linus Y. Liu, Farid K. Abdelmalak,
Michaela A. Diamanti, Kristin Retzlaff, Jürgen Scheller, Stefan
Rose-John, Florian R. Greten, Jean Y. J. Wang, and Lars
Eckmann
J Immunol 2013 191:837-847; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1201716
β-Defensin 2 and 3 Promote the Uptake of Self or CpG DNA,
Enhance IFN-α Production by Human Plasmacytoid
Dendritic Cells, and Promote Inflammation
Poonam Tewary, Gonzalo de la Rosa, Neeraj Sharma, Luis G.
Rodriguez, Sergey G. Tarasov, O. M. Zack Howard, Hidekazu
Shirota, Folkert Steinhagen, Dennis M. Klinman, De Yang, and
Joost J. Oppenheim
J Immunol 2013 191:865-874; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1201648
SARM Is Required for Neuronal Injury and Cytokine
Production in Response to Central Nervous System Viral
Infection
Ying-Ju Hou, Rebecca Banerjee, Bobby Thomas, Carl Nathan,
Adolfo García-Sastre, Aihao Ding, and Melissa B. Uccellini
J Immunol 2013 191:875-883; published ahead of print June 7,
2013, doi:10.4049/jimmunol.1300374
MOLECULAR AND STRUCTURAL IMMUNOLOGY
Neutrophil Recruitment to the Lung in Both C5a- and CXCL1Induced Alveolitis Is Impaired in Vitamin D–Binding Protein–
Deficient Mice
Glenda Trujillo, David M. Habiel, Lingyin Ge, Mahalakshmi
Ramadass, Nancy E. Cooke, and Richard R. Kew
J Immunol 2013 191:848-856; published ahead of print June 10,
2013, doi:10.4049/jimmunol.1202941
TLR4 Signaling Augments Monocyte Chemotaxis by
Regulating G Protein–Coupled Receptor Kinase 2
Translocation
Zheng Liu, Yong Jiang, Yuehua Li, Juan Wang, Liyan Fan,
Melanie J. Scott, Guozhi Xiao, Song Li, Timothy R. Billiar, Mark A.
Wilson, and Jie Fan
J Immunol 2013 191:857-864; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1300790
Conformational Shift of a Major Poliovirus Antigen
Confirmed by Immuno-Cryogenic Electron Microscopy
Jun Lin, Naiqian Cheng, James M. Hogle, Alasdair C. Steven,
and David M. Belnap
J Immunol 2013 191:884-891; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1202014
SASH1 Is a Scaffold Molecule in Endothelial TLR4
Signaling
Shauna M. Dauphinee, Ashley Clayton, Angela Hussainkhel,
Cindy Yang, Yoo-Jin Park, Megan E. Fuller, Josip Blonder,
Timothy D. Veenstra, and Aly Karsan
J Immunol 2013 191:892-901; published ahead of print June 17,
2013, doi:10.4049/jimmunol.1200583
Opposing Roles of STAT4 and Dnmt3a in Th1 Gene
Regulation
Duy Pham, Qing Yu, Crystal C. Walline, Rajarajeswari
Muthukrishnan, Janice S. Blum, and Mark H. Kaplan
J Immunol 2013 191:902-911; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1203229
An Engineered Construct Combining Complement
Regulatory and Surface-Recognition Domains Represents a
Minimal-Size Functional Factor H
Mario Hebecker, María Alba-Domínguez, Lubka T. Roumenina,
Stefanie Reuter, Satu Hyvärinen, Marie-Agnès Dragon-Durey, T.
Sakari Jokiranta, Pilar Sánchez-Corral, and Mihály Józsi
J Immunol 2013 191:912-921; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1300269
TUMOR IMMUNOLOGY
Inflammatory Cytokine–Mediated Evasion of Virus-Induced
Tumors from NK Cell Control
Rabinarayan Mishra, Bojan Polic, Raymond M. Welsh, and Eva
Szomolanyi-Tsuda
J Immunol 2013 191:961-970; published ahead of print June 14,
2013, doi:10.4049/jimmunol.1203328
Tumor-Derived Vascular Pericytes Anergize Th Cells
Anamika Bose, Subhasis Barik, Saptak Banerjee, Tithi Ghosh,
Atanu Mallick, Suchandra Bhattacharyya Majumdar, Kuntal Kanti
Goswami, Avishek Bhuniya, Sayantan Banerjee, Rathindranath
Baral, Walter J. Storkus, Partha Sarathi Dasgupta, and Subrata
Majumdar
J Immunol 2013 191:971-981; published ahead of print June 19,
2013, doi:10.4049/jimmunol.1300280
Trp53 Deficiency Protects against Acute Intestinal Inflammation
Martina E. Spehlmann*,1, Carolin F. Manthey*,2, Sara M. Dann*,3, Elaine Hanson*,
Sukhman S. Sandhu*, Linus Y. Liu*, Farid K. Abdelmalak*, Michaela A. Diamanti†,
Kristin Retzlaff†, Jürgen Scheller‡,4, Stefan Rose-John‡, Florian R. Greten†, Jean Y. J.
Wang§ and Lars Eckmann*
*Department
of Medicine, University of California, San Diego, La Jolla, CA 92093;
†Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University of
Munich, 81675 Munich, Germany; ‡Institute of Biochemistry, Christian-AlbrechtsUniversity of Kiel, 24098 Kiel, Germany; and §Cancer Center, University of California,
San Diego, La Jolla, CA 92093
The p53 protein has not only important tumor suppressor activity but also additional
immunological and other functions, whose nature and extent are just beginning to be
recognized. In this article, we show that p53 has a novel inflammation-promoting action
in the intestinal tract, because loss of p53 or the upstream activating kinase, ATM,
protects against acute intestinal inflammation in murine models. Mechanistically,
deficiency in p53 leads to increased survival of epithelial cells and lamina propria
macrophages, higher IL-6 expression owing to enhanced glucose-dependent NF-κB
activation, and increased mucosal STAT3 activation. Blockade or loss of IL-6 signaling
reverses the protective effects of p53 deficiency. Conversely, IL-6 treatment protects
against acute colitis in a manner dependent on STAT3 signaling and induction of
cytoprotective factors in epithelial cells. Together, these results indicate that p53
promotes inflammation in the intestinal tract through suppression of epitheliumprotective factors, thus significantly expanding the spectrum of physiological and
immunological p53 activities unrelated to cancer formation.
Nature Immunology | Article
GATA-3 controls the maintenance and proliferation of T cells downstream of TCR
and cytokine signaling
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
GATA-3 controls T helper type 2 (TH2) differentiation. However, whether GATA-3 regulates the function of mature T
cells beyond TH2 determination remains poorly understood. We found that signaling via the T cell antigen receptor
(TCR) and cytokine stimulation promoted GATA-3 expression in CD8+ T cells, which controlled cell proliferation.
Although GATA-3-deficient CD8+ T cells were generated, their peripheral maintenance was impaired, with lower
expression of the receptor for interleukin 7 (IL-7R). GATA-3-deficient T cells had defective responses to viral infection
and alloantigen. The proto-oncoprotein c-Myc was a critical target of GATA-3 in promoting T cell proliferation. Our
study thus demonstrates an essential role for GATA-3 in controlling the maintenance and proliferation of T cells and
provides insight into immunoregulation.