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| Open AccessKenny mediates selective autophagic degradation of the IKK complex to control innate immune responses
Selective autophagy describes the selective degradation of cellular components upon stress or nutrient deficiency, but whether it modulates innate immunity is unclear. Here the authors show that Drosophila Kenny may be an evolution-selected autophagy receptor for the down-regulation of innate NF-κB activation
- Radu Tusco
- , Anne-Claire Jacomin
- & Ioannis P. Nezis
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Article
| Open AccessNMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury
Damage-associated molecular patterns (DAMP) are important mediators of innate immunity. Here the authors show that N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs to promote inflammation by activating macrophages via the Toll-like receptor 4 and NF-κB pathways.
- Zhikai Xiahou
- , Xiangli Wang
- & Huanhuan Liang
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Article
| Open AccessRegulation of T cell alloimmunity by PI3Kγ and PI3Kδ
Phosphatidylinositol-3-kinases (PI3K) γ and δ are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kγ or PI3Kδ deficiency prolongs graft survival, but selective inhibition of PI3Kγ or PI3Kδ reveals alternative transplant survival outcomes post CTLA4-Ig treatment.
- Mayuko Uehara
- , Martina M. McGrath
- & Reza Abdi
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Article
| Open AccessArginine methylation catalyzed by PRMT1 is required for B cell activation and differentiation
PRMT1 is an arginine methyltransferase involved in a variety of cell functions. Here the authors delete PRMT1 specifically in mature B cells to show the importance of arginine methylation for B cell proliferation, differentiation and survival, and thereby for humoral immunity.
- Simona Infantino
- , Amanda Light
- & David Tarlinton
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Article
| Open AccessAn NF-κB-microRNA regulatory network tunes macrophage inflammatory responses
MicroRNAs (miR) are important regulators of gene transcription, with miR-155 and miR-146a both implicated in macrophage activation. Here the authors show that NF-κB signalling, miR-155 and miR-146a form a complex network of cross-regulations to control gene transcription in macrophages for modulating inflammatory responses.
- Mati Mann
- , Arnav Mehta
- & David Baltimore
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Article
| Open AccessNFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia
NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.
- Melanie Märklin
- , Jonas S. Heitmann
- & Martin R. Müller
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Article
| Open AccessNFATc1 controls the cytotoxicity of CD8+ T cells
NFAT nuclear translocation has been shown to be required for CD8+ T cell cytokine production in response to viral infection. Here the authors show NFATc1 controls the cytotoxicity and metabolic switching of activated CD8+ T cells required for optimal response to bacteria and tumor cells.
- Stefan Klein-Hessling
- , Khalid Muhammad
- & Edgar Serfling
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Article
| Open AccessSignalling strength determines proapoptotic functions of STING
The cGAS/STING signalling pathway is responsible for sensing intracellular DNA and activating downstream inflammatory genes. Here the authors show mouse primary T cells and T leukaemia are hyperresponsive to STING agonist, and this strong STING signalling is associated with apoptosis induction.
- Muhammet F. Gulen
- , Ute Koch
- & Andrea Ablasser
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Article
| Open AccessLyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation
Src-family kinases Fyn and Lyn are signaling components downstream of ITAM-bearing antigen receptors. Here the authors show that by phosphorylating SHP-1 at different residues, Lyn and Fyn can have opposing regulatory effects on ITAM receptors.
- Sanae Ben Mkaddem
- , Amaya Murua
- & Renato C. Monteiro
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Article
| Open AccessCLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation
The NLRP3 inflammasome is key to the regulation of innate immunity against pathogens or stress, but the underlying signaling regulation is still unclear. Here the authors show that chloride intracellular channels (CLIC) interface between mitochondria stress and inflammasome activation to modulate inflammatory responses.
- Tiantian Tang
- , Xueting Lang
- & Rongbin Zhou
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Article
| Open AccessLkb1 maintains Treg cell lineage identity
The protein kinase Lkb1 has been shown to limit conventional T cell activation and pro-inflammatory functions. Here the authors show that Lkb1 also maintains Foxp3 expression and suppressive function in regulatory T (Treg) cells, and that Treg-specific Lkb1-deficient mice develop fatal autoimmune disease.
- Di Wu
- , Yuechen Luo
- & Xiaoming Feng
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Article
| Open AccessMultiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling
MAVS is an essential component of the pathogen-sensing machinery, and functions by forming prion-like filaments. Here the authors show that alternatively translated forms of truncated endogenous MAVS can prevent spontaneous aggregation and degradation in cells to sustain MAVS-mediated immune signalling.
- Nan Qi
- , Yuheng Shi
- & Fajian Hou
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Article
| Open AccessTespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors
The thymocyte development protein Tespa1 is known to translate T cell receptor signals by affecting the calcium signalling cascade, but it is not clear how. Here the authors show that Tespa1 recruits IP3R1 to the TCR signalling complex.
- Jingjing Liang
- , Jun Lyu
- & Linrong Lu
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Article
| Open AccessThe PYRIN domain-only protein POP2 inhibits inflammasome priming and activation
Excessive inflammasome activation leads to inflammatory diseases, but how inflammasomes are regulated by PYD-only adaptors is unclear. Here the authors show that the PYD-only protein POP2 inhibits both inflammasome priming and assembly by interfering, respectively, with IκBα activation and NLRP3-ASC interaction.
- Rojo A. Ratsimandresy
- , Lan H. Chu
- & Christian Stehlik
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Article
| Open AccessThe ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells
γδT cells are activated by phosphoantigens, and ABCA1 is involved in cholesterol transport. Here the authors link these ideas to show that ABCA1, apoA-I and BTN3A1 regulate extracellular phosphoantigen release by dendritic cells, and implicate ABCA1 in mevalonate-mediated activation of Vγ9Vδ2 T cells.
- Barbara Castella
- , Joanna Kopecka
- & Massimo Massaia
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Article
| Open AccessNdfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease
T regulatory (Treg) cells are essential for maintaining immune homeostasis, but how the stability of their lineage and function is regulated is unclear. Here the authors show that Ndfip1 is essential for suppressing Tregcell IL-4 production and metabolic alteration to preserve Treg lineage and function.
- Awo Akosua Kesewa Layman
- , Guoping Deng
- & Paula M. Oliver
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| Open AccessExpression of CD226 is associated to but not required for NK cell education
CD226 is an activating receptor expressed in a co-varied manner with inhibitory receptors on natural killer (NK) cells, but whether CD226 is involved in NK cell education is unclear. Here the authors show that CD226 expression is plastic depending on the MHC environment and endows educated NK cells enhanced effector functions.
- Arnika K. Wagner
- , Nadir Kadri
- & Benedict J. Chambers
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Article
| Open AccessAn allosteric site in the T-cell receptor Cβ domain plays a critical signalling role
Binding of T cell receptors (TCR) to peptide-loaded major histocompatibility complexes (p/MHC) leads to T-cell activation. Here the authors give structural insights into T-cell signalling and show that p/MHC binding induces conformational changes at the membrane-proximal site of the TCR.
- Kannan Natarajan
- , Andrew C. McShan
- & Nikolaos G. Sgourakis
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| Open AccessPEGylated graphene oxide elicits strong immunological responses despite surface passivation
Polyethylene glycol has been widely utilized to functionalize nanomaterials in order to improve their biocompatibility. Here, the authors demonstrate that PEGylated nano-graphene oxide can elicit an inflammatory response, contradicting current literature.
- Nana Luo
- , Jeffrey K. Weber
- & Guanghui Ma
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Article
| Open AccessCleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death
DFNA5 is related to the caspase-dependent pyroptosis inducer gasdermin D. Here the authors find that DFNA5 is cleaved by caspase 3 and show this cleavage skews cells away from apoptosis into secondary necrosis, a form of cell death characterized by membrane ballooning similar to pyroptosis.
- Corey Rogers
- , Teresa Fernandes-Alnemri
- & Emad S. Alnemri
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Article
| Open AccessLinear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis
LUBAC is a ubiquitin ligase complex of HOIL-1, HOIP and SHARPIN important for signal transduction of a range of stimuli. Here the authors define the function of all three LUBAC components in T cell development and homeostasis.
- Charis E. Teh
- , Najoua Lalaoui
- & Daniel H. D. Gray
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Article
| Open AccessProtein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1
The three isoforms of protein kinase D (PKD) have important but often redundant roles in cell signalling. Here the authors show, by generating PKD2/3 double-deficient mice, that PKD is essential for TCR signalling in thymocytes, and identify SHP-1 as a PKD target critical for development of CD4+T cells.
- Eri Ishikawa
- , Hidetaka Kosako
- & Sho Yamasaki
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Article
| Open AccessSuper-resolution microscopy reveals a preformed NEMO lattice structure that is collapsed in incontinentia pigmenti
NEMO is a member of the IKK complex that binds ubiquitin, involved in NF-κB signalling and proposed to form higher order structures. Here the authors use super-resolution microscopy to detect the presence of NEMO lattices in cells, that are modified by NF-κB treatment and abrogated by mutations affecting NEMO ubiquitin binding.
- Janine Scholefield
- , Ricardo Henriques
- & Musa M. Mhlanga
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Article
| Open AccessSignal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states
In biological systems, timing is often critical to the interpretation of signals that determine cell fate. Here the authors demonstrate how single cells and cellular populations respond dynamically to pulsatile stimulation by TNFα and IL-1β, and suggest a mechanism by which the two cytokines can synergistically modulate inflammation.
- Antony Adamson
- , Christopher Boddington
- & Pawel Paszek
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Article
| Open AccessStepwise phosphorylation of p65 promotes NF-κB activation and NK cell responses during target cell recognition
NK cell activation requires multiple signals. Here the authors show that while NKG2D, 2B4, or DNAM-1 receptor activation is insufficient to induce cytokine production, these signals synergize by Vav-1-mediated NF-κB multiphosphorylation, and this signaling checkpoint is defective in X-linked lymphoproliferative disease.
- Hyung-Joon Kwon
- , Go-Eun Choi
- & Hun Sik Kim
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Article
| Open AccessCXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation
T cell development has been a classical model for understanding cell fate regulation by epigenetics. Here the authors show that Cxxc1 controls thymocyte development mainly through regulating several key genes, such as Rorc, Zap70 and Cd8, which requires its H3K4me3 but not DNA methylation function.
- Wenqiang Cao
- , Jing Guo
- & Lie Wang
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Article
| Open AccessNrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.
- Eri H. Kobayashi
- , Takafumi Suzuki
- & Masayuki Yamamoto
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| Open AccessT-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine
How transcription factor T-bet and Th17 cells contribute to colitis remains incompletely understood. Here the authors identify T-bet as a negative regulator of IL-23R pathway activation and show that T-bet deficient T cells drive colitogenic Th17 responses dependent on the cytokines IL-17A and IL-22.
- Thomas Krausgruber
- , Chris Schiering
- & Fiona Powrie
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Article
| Open AccessVirtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner
Virtual memory T cells are CD8 T cells with memory phenotype present in unimmunized mice. Here the authors show that these cells have higher affinity for self-antigen, depend on IL-15 for proliferation and antigen-non-specific cytotoxicity in mice, and that a similar population exists in humans.
- Jason T. White
- , Eric W. Cross
- & Ross M. Kedl
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Article
| Open AccessStructural basis of complement membrane attack complex formation
The membrane attack complex (MAC) is an immune effector that kills pathogens by forming pores in their membrane. Here the authors use cryo-electron microscopy to reveal that the full MAC is an asymmetric pore with a split-washer configuration and identify a network of interactions that provide a basis for sequential assembly.
- Marina Serna
- , Joanna L. Giles
- & Doryen Bubeck
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Article
| Open AccessAKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation
A-kinase anchoring protein 9 (AKAP9) is a scaffold protein that binds signalling proteins and regulates microtubules. Here the authors show that during inflammation AKAP9 in T cells is required for their reactivation and retention at the inflammation site and that its deletion protects from inflammation-induced organ damage.
- Jan M. Herter
- , Nir Grabie
- & Tanya N. Mayadas
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| Open AccessNatural cytotoxicity receptor splice variants orchestrate the distinct functions of human natural killer cell subtypes
Decidual natural killer (NK) cells from the pregnant uterus play an important role in the physiology of pregnancy and differ functionally from peripheral blood NK cells. Siewiera et al. reveal that this is partly due to the differential expression of splice variants of natural cytotoxicity receptors by these two cell subsets.
- Johan Siewiera
- , Jordi Gouilly
- & Nabila Jabrane-Ferrat
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Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation
Tissue-resident B-1 cells express CD11b, unlike their lymphoid organ-residing counterparts. Here the authors show that influenza-induced type I interferons activate CD11b on B-1 cells, facilitating entry to mediastinal lymph nodes, where they provide the first line of antibody-mediated host defense.
- Elizabeth E. Waffarn
- , Christine J. Hastey
- & Nicole Baumgarth
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| Open AccessThe paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling
MALT1 mediates NFκB activation. Here the authors perform proteomic analysis of human immunodeficient mutant MALT1 B cells revealing that MALT1 cleaves the HOIL1 subunit of the linear ubiquitin chain assembly complex to dampen late NFκB activation and to invoke negative feedback of NFκB activation.
- Theo Klein
- , Shan-Yu Fung
- & Christopher M. Overall
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| Open AccessHuman caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes
Human monocytes exhibit an unconventional one-step pathway of inflammasome activation and IL-1 release in response to LPS. Here the authors show that it is mediated by caspases 4 and 5, and characterize caspase 5 cleavage, Syk and calcium signalling as key mediators of this pathway.
- Elena Viganò
- , Catherine Emma Diamond
- & Alessandra Mortellaro
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Article
| Open AccessReactivation of IgG-switched memory B cells by BCR-intrinsic signal amplification promotes IgG antibody production
Antigen receptors on memory B cells enhance their signaling strength by recruiting the cytosolic Grb2 adaptor to their ITT phosphorylation motifs. Here the authors show that inactivating the ITT motif of mouse mIgG1 impairs IgG1 production and T-cell independent reactivation of memory B cells.
- Johannes Lutz
- , Kai Dittmann
- & Niklas Engels
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Article
| Open AccessAntigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1
Antigen stimulation in vivocan reprogram T regulatory cells to lose the expression of Foxp3 and become effector cells. Here the authors show that the mechanism involves dephosphorylation of STAT5 by PTPN2 and downregulation of Foxo1 by miR-182.
- Evita Bothur
- , Hartmann Raifer
- & Michael Lohoff
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Article |
Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth
NF-κB has largely been known as a transcriptional activator. Here the authors show that a transcriptionally repressive NF-κB complex, HDAC4–RelB–p52, maintains repressive chromatin at proapoptotic genes Bim and BMF, and regulates multiple myeloma survival and growth in an ERK1 dependent manner.
- Subrahmanya D. Vallabhapurapu
- , Sunil K. Noothi
- & Sivakumar Vallabhapurapu
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Article
| Open AccessCyclic diguanylate monophosphate directly binds to human siderocalin and inhibits its antibacterial activity
Siderocalin is an antibacterial component of the innate immune system that prevents iron acquisition by bacteria by sequestering their iron-binding siderophores. Here, Li et al.show that the bacterial second messenger c-di-GMP binds to siderocalin, thus inhibiting its antibacterial function.
- Weihui Li
- , Tao Cui
- & Zheng-Guo He
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Article
| Open AccessGITR subverts Foxp3+ Tregs to boost Th9 immunity through regulation of histone acetylation
Glucocorticoid-induced TNFR-related protein (GITR), a costimulatory protein expressed by T cells, has immunostimulatory effect but the underlying mechanism is not clear. Here the authors show that GITR ligation inhibits the induction of Foxp3 expression and diverts CD4 T cells towards Th9 differentiation instead of iTreg.
- Xiang Xiao
- , Xiaomin Shi
- & Xian Chang Li
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Article
| Open AccessStructural mechanism for signal transduction in RXR nuclear receptor heterodimers
Some nuclear receptors dimerize with retinoid X receptor to allow ligand-dependent signalling. Here, Kojetin et al.use structural and biophysical techniques to identify structural changes that guide these complex signalling networks.
- Douglas J. Kojetin
- , Edna Matta-Camacho
- & Kendall W. Nettles
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Article
| Open AccessIL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells
The proinflammatory cytokine interleukin-1ß (IL-1ß) plays an important role in host defence against pathogens. Here the authors report a non-canonical pathway for IL-1 ß production in conventional dendritic cells that is induced by IL-21 via STAT3-dependent mechanism.
- Chi-Keung Wan
- , Peng Li
- & Warren J. Leonard
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Article
| Open AccessIL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis
Pathological neovascularization causes blinding eye disease. Here the authors show that IL10 activates STAT3 signalling in the macrophages in the ageing eye, promoting their polarization towards a pro-angiogenic phenotype; interfering with this pathway reverses the pathology in a mouse model.
- Rei Nakamura
- , Abdoulaye Sene
- & Rajendra S. Apte
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Article
| Open AccessThe mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling
RNA viral infections trigger an immune response mediated by the formation of aggregates of the MAVS protein. Here the authors show that the mitochondrial protein MARCH5 modulates this response by transferring ubiquitin to MAVS aggregates, thus promoting their proteasomal degradation.
- Young-Suk Yoo
- , Yong-Yea Park
- & Hyeseong Cho
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Article
| Open AccessPhosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation
TGF-ß and IL-6 are the essential cytokines for mediating the differentiation of IL-17-producing CD4+ T helper cells (TH17). Here, Yoon et al. provide more insights into this process and describe the opposing roles of TGFß-signalling intermediates Smad2 and Smad3 as STAT3 cofactors in Th17 differentiation.
- Jeong-Hwan Yoon
- , Katsuko Sudo
- & Mizuko Mamura
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Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation
Syndecan-4 is a surface protein implicated in the regulation of cytoskeleton, adhesion and migration. Here the authors show that blocking syndecan-4 prevents dendritic cell migration into the lung and inhibits the development of allergic airway inflammation in mice.
- Tobias Polte
- , Susanne Petzold
- & Marco Averbeck
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Article
| Open AccessNF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis
Psoriasis is accompanied by NF-κB activation and hyperplasia. Here the authors show that NF-κB transcriptionally activates miR-31, which downregulates a negative cell cycle regulator protein phosphatase 6, and that this is critical for NF-κB to drive keratinocyte hyperproliferation.
- Sha Yan
- , Zhenyao Xu
- & Honglin Wang
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| Open AccessCaspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3
Inflammasome activation requires a complex and incompletely understood network of signalling events. Here the authors characterize step-by-step contributions of TLR3, caspase-8, RIPK3 and MLKL to the activation of NLRP3 inflammasome in response to double-stranded RNA.
- Seokwon Kang
- , Teresa Fernandes-Alnemri
- & Emad S. Alnemri
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Article
| Open AccessExpression of the vault RNA protects cells from undergoing apoptosis
Cellular functions of the vault complex, a large ribonucleoprotein assembly remain elusive. Here, the authors show that Epstein–Barr virus infection enhances the expression of the vault complex-associated RNAs, which leads to improved survival of infected cells due to the inhibition of cell apoptosis.
- Melanie Amort
- , Birgit Nachbauer
- & Norbert Polacek