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| Open AccessDetermining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB
Dorsal organizer initiates the dorsal-ventral axis formation in vertebrates. Here, the authors demonstrate that Tlr4/NFκB-mediated negative feedback regulation of Wnt/β-catenin signaling determines the precise size of the zebrafish dorsal organizer.
- Juqi Zou
- , Satoshi Anai
- & Tohru Ishitani
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Article
| Open AccessToll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses
Compared to germinal centres, extrafollicular plasmablast responses are thought to produce lower affinity antibodies, offering little protection from infection. Here authors show in an influenza infection and immunization mouse model that extrafollicular responses could yield protective antibodies, and that their development depends on signals provided via Toll-like receptor stimulation.
- Jonathan H. Lam
- & Nicole Baumgarth
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| Open AccessCXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes
The chemokine, CXCL4, is proposed to enhance Toll-like receptor (TLR) signaling by facilitating TLR ligand import. Here the authors show that CXCL4 also synergizes with TLR8 to promote the activation of TBK1 and IKKε and induce epigenetic remodeling of relevance inflammatory genes to enhance inflammatory responses in human monocytes.
- Chao Yang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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| Open AccessN4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization
NF-κB signalling is critical to TLR mediated cytokine release in various immune responses. Here the authors show how N4BP1 inhibits NEMO signalling and subsequent NF-κB activation and how this pathway is negatively regulated by caspase-8 cleavage of N4BP1.
- Hexin Shi
- , Lei Sun
- & Bruce Beutler
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| Open AccessQuantifying information accumulation encoded in the dynamics of biochemical signaling
Understanding how cells discriminate between stimuli is an ongoing challenge. Here, the authors propose a mathematical framework for inferring the mutual information encoded in temporal signaling dynamics and use it to study how information is transmitted over time in response to different stimuli in NFκB, MAPK and p53 signaling pathways.
- Ying Tang
- , Adewunmi Adelaja
- & Alexander Hoffmann
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Article
| Open AccessNFAT primes the human RORC locus for RORγt expression in CD4+ T cells
The master transcription factor RORγt, encoded by the RORC gene, controls the polarization of CD4+ T cells expressing interleukin-17 (Th17). Here the authors describe several regulatory elements at the RORC locus that are recognized by NFAT and NFkB to induce a permissive epigenetic configuration of the RORC gene for RORγt expression and Th17 differentiation.
- Hanane Yahia-Cherbal
- , Magda Rybczynska
- & Elisabetta Bianchi
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| Open AccessExtracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation
The enzyme nicotinate phosphoribosyltransferase (NAPRT) mediates the rate-limiting step in NAD salvage pathway starting from nicotinic acid. Here the authors show that NAPRT can be detected extracellularly, binds to Toll like receptor 4, and activates NF-kB signaling and cytokine production in macrophage via NAD synthesis-independent pathways.
- Antonella Managò
- , Valentina Audrito
- & Silvia Deaglio
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Article
| Open AccessBcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells
The differentiation and function of regulatory T (Treg) cells are critically controlled by T cell receptor (TCR) signaling. Here the authors show that CARD11-BCL10-MALT1 (CBM) complexes are dispensable for effector Treg conversion under inflammatory conditions but are critical for mediating Treg suppressive activity in a MALT1 paracaspase-dependent manner.
- Marc Rosenbaum
- , Andreas Gewies
- & Jürgen Ruland
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Article
| Open AccessIL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling
CD4+ helper T cells producing IL-9 (Th9) have been implicated in anti-tumor immunity, with Th9 differentiation inducible in vitro via IL-4 and TGFβ treatment. Here the authors show that replacing TGFβ with IL-1β induces a distinct IL-9+ CD4+ population that have strong cytotoxic and anti-tumor activity in preclinical mouse models.
- Gang Xue
- , Guangxu Jin
- & Yong Lu
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Article
| Open AccessHectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation
Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.
- Jonathan J. Cho
- , Zhiwei Xu
- & Dorina Avram
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Article
| Open AccessIntestinal non-canonical NFκB signaling shapes the local and systemic immune response
Microfold cells (M-cell) are specialized cells of the intestine that sample luminal microbiota and dietary antigens. Here the authors show that epithelial non-canonical NFκB signalling, as induced by NIK, is important for M-cells maintenance, yet constitutive NIK activation is associated with gut inflammation and inflammatory bowel disease.
- Sadeesh K. Ramakrishnan
- , Huabing Zhang
- & Yatrik M. Shah
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| Open AccessControl of Treg cell homeostasis and immune equilibrium by Lkb1 in dendritic cells
Regulatory T (Treg) cells are important for maintaining immune homeostasis by suppressing immune cell activation, but how the Treg cell pool is maintained is still unclear. Here the authors show that a kinase, Lkb1, operates in dendritic cells (DC) to inhibit Treg cell expansion and immunosuppression via mechanisms involving NF-kB/OX40L signalling.
- Song Chen
- , Lijun Fang
- & Xiaoming Feng
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| Open AccessCyclophilin J limits inflammation through the blockage of ubiquitin chain sensing
Nuclear factor-kappa B (NF-κB) signaling is regulated by ubiquitin to maintain immune homeostasis. Here the authors show that a peptidylprolyl isomerase, CYPJ, blocks TAB2/3 or LUBAC ubiquitin chain sensing and suppress NF-κB activation, with CYPJ-deficiency leading to susceptibility to inflammatory stimuli.
- Chunjie Sheng
- , Chen Yao
- & Shuai Chen
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Article
| Open AccessMolecular architecture and regulation of BCL10-MALT1 filaments
The BCL10-MALT1 complex is a central signaling hub in lymphocytes and linked to various human immune pathologies. Here the authors present the cryo-EM structure of the BCL10-MALT1 filament core and verify the identified BCL10/MALT1 interface with mutagenesis studies.
- Florian Schlauderer
- , Thomas Seeholzer
- & Katja Lammens
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Article
| Open AccessNF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model
The molecular mechanisms leading to heart failure in patients with Duchenne muscular dystrophy are unclear. Here the authors show that NF-κB is activated in the heart of dystrophin-deficient mice and that its ablation rescues cardiac function through chromatin remodeling and activation of gene expression.
- Jennifer M. Peterson
- , David J. Wang
- & Denis C. Guttridge
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| Open AccessRegulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling
Lymphotoxin beta receptor (LTβR) signalling regulates leukocyte migration through the lymphatic endothelial layers. Here, the authors show that treatment of an LTβR-derived decoy peptide can target the non-classical NFκB pathway to inhibit T cell and dendritic cell migration and ameliorate contact hypersensitivity in mouse models.
- Wenji Piao
- , Yanbao Xiong
- & Jonathan S. Bromberg
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| Open AccessA TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling
The innate immunity system detects viral pathogens by sensing viral DNA or RNA via distinct pathways, but whether these pathways cross-regulate is unclear. Here the authors show that TRAF3, a known regulator of the RNA-sensing pathway, modulates an NF-κB activator NIK to control DNA-sensing by the adaptor STING in immune cells.
- Kislay Parvatiyar
- , Jose Pindado
- & Genhong Cheng
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| Open AccessPeli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disorder mediated by excessive autoantibodies. Here the authors show that an E3 ubiquitin ligase, Peli1, negatively modulates noncanonical NF-κB signaling to restrain lupus-like symptoms in mice, and that Peli1 expression inversely correlates with SLE severity in humans.
- Junli Liu
- , Xinfang Huang
- & Yichuan Xiao
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| Open AccessA non-conserved amino acid variant regulates differential signalling between human and mouse CD28
CD28 transmits co-stimulatory signals for the activation of both mouse and human T cells, but in vivo hyperactivation of CD28 has opposite effects on system immunity. Here, the authors show that a single amino acid difference between mouse and human CD28 dictates this function distinction via differential recruitment of Nck.
- Nicla Porciello
- , Paola Grazioli
- & Loretta Tuosto
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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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| 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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| 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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| 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 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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| 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 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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| 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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| 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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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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| 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 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
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IκBβ enhances the generation of the low-affinity NFκB/RelA homodimer
The NFκB signalling pathway is regulated through the formation of transcription factor dimers but mechanisms controlling their formation are poorly understood. Here, Tsui et al. report that IκBb is a positive regulator of Rel-NFκB dimer formation, using in vitro and in vivoexperiments and mathematical modelling.
- Rachel Tsui
- , Jeffrey D. Kearns
- & Alexander Hoffmann
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| Open AccessNFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma
The role of neutrophils in cancer development is not widely appreciated. Here, the authors show that NF-κB-deficient hepatocytes overproduce chemokines, leading to hepatocellular carcinoma due to excessive neutrophil recruitment, and that neutrophil depletion prevents liver cancer in these mice.
- C. L. Wilson
- , D. Jurk
- & D. A. Mann
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The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF
The importance of the post-translational modification by acetylation in regulating protein function is not fully understood. Here, the authors show that acetylation of the transcriptional factor PLZF promotes the assembly of a repressor complex that limits the inflammatory response mediated by NF-κB.
- Anthony J. Sadler
- , Bandar A. Suliman
- & Dakang Xu
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| Open AccessThe interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation
Human papillomavirus employs immune evasion strategies to establish a long-term infection. Here the authors show that the virus in the EGFR-dependent manner induces IFRD1, which blocks NFκB activating acetylation, and that this process can be suppressed by the EGFR inhibitor cetuximab.
- Bart Tummers
- , Renske Goedemans
- & Sjoerd H. van der Burg
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Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9
ß-TrCP is an adaptor protein that controls activity of several key regulatory proteins including NFκB by ubiquitin-mediated proteolysis. Here Shi et al. demonstrate that ß-TrCP is negatively regulated by the brain-specific protein TRIM9, limiting activation of NFκB and production of proinflammatory cytokines.
- Mude Shi
- , Hyelim Cho
- & Jae U. Jung
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NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype
Aggressive types of breast cancer often exhibit constitutive activation of the pro-inflammatory transcription factor NF-κB. Here, Yamamoto et al. show that, in basal-like breast cancer, NF-κB upregulates the Notch receptor ligand JAG1 in non-cancer stem cells and thereby induces proliferation of breast cancer stem cells.
- Mizuki Yamamoto
- , Yuu Taguchi
- & Jun-ichiro Inoue
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Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells
The NF-κB complex is a core regulator of inflammatory gene expression and activates transcription of many different target genes. Fu et al. show that NF-κB promoter specificity can be tuned by Sam68, which is required for targeting NF-κB to the CD25 promoter during T cell activation.
- Kai Fu
- , Xin Sun
- & Fengyi Wan
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PPARγ is an E3 ligase that induces the degradation of NFκB/p65
NFκB/p65 and PPARγ are both transcription factors that perform distinct but overlapping roles in cellular regulation. Hou et al. report that PPARγ acts as an E3 ubiquitin ligase and promotes Lys48-linked ubiquitination and degradation of p65, terminating NFκB-mediated inflammation and tumorigenesis.
- Yongzhong Hou
- , France Moreau
- & Kris Chadee