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USP11 regulates PML stability to control Notch-induced malignancy in brain tumours
The tumour suppressor PML is regulated by post-translational modification but the mechanism is unclear. Here, the authors show that PML is deubiquitinated and stabilized by USP11, which is in turn negatively regulated by the Notch signalling pathway.
- Hsin-Chieh Wu
- , Yu-Ching Lin
- & Ruey-Hwa Chen
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The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis
Lgr5 is a protein that is important for the maintenance of intestinal homeostasis. In this study, the authors demonstrate that Lgr5 is required for colorectal cancer development and its expression is regulated by the transcription factor GATA6.
- Shinnosuke Tsuji
- , Yoshihiro Kawasaki
- & Tetsu Akiyama
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MafB promotes atherosclerosis by inhibiting foam-cell apoptosis
In the early stages of atherosclerosis, macrophages in the vessel wall convert into foam cells, which promote the rise of atherosclerotic plaques. Here Hamada et al. show that the macrophage transcription factor MafB inhibits foam-cell apoptosis, and that its absence promotes atherosclerosis development in mice.
- Michito Hamada
- , Megumi Nakamura
- & Satoru Takahashi
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| Open AccessTRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins
Gram-negative bacterial infections can often cause inflammation and pain. Meseguer et al. show that the inflammation and pain result from the direct activation of nociceptor TRPA1 channels by lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria.
- Victor Meseguer
- , Yeranddy A. Alpizar
- & Félix Viana
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A dual role for autophagy in a murine model of lung cancer
Autophagy prolongs the survival of cells in stressful conditions but its role in cancer is unclear. Here, Rao et al. show that loss of the autophagic protein Atg5 enhanced cancer incidence but impaired tumour progression in a mouse model of lung cancer.
- Shuan Rao
- , Luigi Tortola
- & Josef M. Penninger
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Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne
Severe acne is a common skin disease characterized by chronic inflammation and potential scarring. Here, the authors have identified genetic variants at two loci associated with severe acne and provide insight into the genetic architecture and biological pathways underlying the disease.
- Li He
- , Wen-Juan Wu
- & Ya-Ping Zhang
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FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours
The majority of ovarian granulosa tumours harbour the C134W mutation in FOXL2 but the mechanism of tumorigenesis is largely unknown. Here, Kim et al. show that mutant FOXL2 is hyperphosphorylated by GSK3β, which targets the protein for degradation, and find that GSK3β inhibition represses the growth of ovarian granulosa cells.
- Jae-Hong Kim
- , Yong-Hak Kim
- & Jeehyeon Bae
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Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis
Mdm2 controls the levels of the tumour suppressor p53 in cells and p53 is often mutated in cancer. Here, Zheng et al. show that a particular Mdm2 isoform that is altered in cancer leads to elevated levels of mutant p53 protein and enhanced gain-of-function of the protein.
- Tongsen Zheng
- , Jiabei Wang
- & Wenwei Hu
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Transcription factors FOXG1 and Groucho/TLE promote glioblastoma growth
Glioblastoma cancers contain brain tumour-initiating cells and targeting these specific cells is an attractive opportunity for therapy. In this study, the authors show that FOXG1 and Groucho/TLE transcription factors are important for glioblastoma growth and might be useful therapeutic targets.
- Federica Verginelli
- , Alessandro Perin
- & Stefano Stifani
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The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis
Gene expression in the vascular endothelium is sensitive to shear forces exerted by the circulation. Here the authors identify miR-712 as a mechanosensitive microRNA expressed in endothelial cells and show that miR-712 inhibits pro-atherogenic processes by downregulating tissue inhibitor of metalloproteinase 3.
- Dong Ju Son
- , Sandeep Kumar
- & Hanjoong Jo
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| Open AccessRETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Pericytes are cells in the blood–brain barrier that degenerate with the onset of Alzheimer's disease. Here, Sagare et al. show that pericyte loss contributes to disease onset by promoting amyloid-beta accumulation, tau pathology and early loss of neuronal cells.
- Abhay P. Sagare
- , Robert D. Bell
- & Berislav V. Zlokovic
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| Open AccessA failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice
Defective ascorbic acid flux is a sign of metabolic failure associated with Huntington’s disease. Here, Acuña et al.show that reduction in ascorbic acid flux from astrocytes precedes the symptoms of Huntington’s disease in mice and impairs ascorbic acid uptake in neurons.
- Aníbal I. Acuña
- , Magdalena Esparza
- & Maite A. Castro
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Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.
- Ingmar Mederacke
- , Christine C. Hsu
- & Robert F. Schwabe
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| Open AccessGenome-wide association study implicates NDST3 in schizophrenia and bipolar disorder
Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3in severe psychiatric disease.
- Todd Lencz
- , Saurav Guha
- & Ariel Darvasi
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Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
The enzyme NEU1 negatively regulates lysosomal exocytosis in various cell types. Annunziata et al.show that mice deficient in NEU1 display Alzheimer’s disease-like pathology and that direct brain administration of NEU1 reduces pathology in an Alzheimer’s disease mouse model.
- Ida Annunziata
- , Annette Patterson
- & Alessandra d’Azzo
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Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation
Misfolding and aggregation of TAR DNA-binding protein 43 is implicated in various neurodegenerative diseases. Chang et al. show that aggregation of this protein is regulated by heat-shock proteins, which act to reduce the amount of pathological protein aggregates.
- Hsiang-Yu Chang
- , Shin-Chen Hou
- & I-Fan Wang
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Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress
Large insoluble aggregates of huntingtin are believed to contribute to the onset of Huntington’s disease, partly by interfering with endoplasmic reticulum-associated protein degradation. Leitman et al.show that huntingtin interferes with protein degradation before it forms insoluble aggregates.
- Julia Leitman
- , F. Ulrich Hartl
- & Gerardo Z. Lederkremer
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Rb1 family mutation is sufficient for sarcoma initiation
Loss of the tumour suppressor Rb1 alone is thought to be insufficient for tumorigenesis. In this study, Liu et al. demonstrate that cells in which all three Rb1 family members are inactivated can initiate tumour formation, but only if cell survival is ensured by the retention of cell–cell contacts.
- Yongqing Liu
- , Ester Sánchez-Tilló
- & Douglas C. Dean
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| Open AccessAkt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency
The PTEN/Akt signalling pathway has been implicated in the pathogenesis of gastric cancer. Here, Guo et al. show that activation of Akt signalling results in the dysregulation of miR-365, which promotes tumorigenesis and that miR-365 reduction correlates with advance-stage tumours in gastric cancer patients.
- Shui-Long Guo
- , Hui Ye
- & Xiao Yang
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Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop
Autoimmune T cell receptors can interact with both self and microbial antigens, but the structural basis for crossreactivity is not fully understood. Here, the authors provide structural insights into binding characteristics of the autoreactive T cell receptor Hy.1B11 to both self and pathogen-derived peptides.
- Dhruv K. Sethi
- , Susana Gordo
- & Kai W. Wucherpfennig
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Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice
The enzyme Elovl6 catalyses a rate-limiting step in the elongation of fatty acids. Here Sunaga et al. show that Elovl6 knockout mice are more susceptible to pulmonary fibrosis, suggesting that the dysregulation of lipid components impairs alveolar epithelial cell function and pulmonary homeostasis.
- Hiroaki Sunaga
- , Hiroki Matsui
- & Masahiko Kurabayashi
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| Open AccessApical membrane antigen 1 mediates apicomplexan parasite attachment but is dispensable for host cell invasion
Plasmodium and Toxoplasma apical membrane antigen 1 (AMA1) is believed to be actively involved in host cell invasion by these parasites. Bargieri et al. now demonstrate that although AMA1 facilitates adhesion, invasion can proceed in the absence of the protein.
- Daniel Y. Bargieri
- , Nicole Andenmatten
- & Robert Ménard
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ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48
ORMDL3has been identified as a gene associated with asthma susceptibility, but its exact role in the pathogenesis of this disease is not well known. Here, the authors propose that induction of ORMDL3 in eosinophils modulates the expression of integrins, which could contribute to a key inflammatory event in asthma.
- Sung Gil Ha
- , Xiao Na Ge
- & P. Sriramarao
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| Open AccessAmyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity
Prion protein has been suggested to bind toxic amyloid-ß oligomers. Nicollet al.demonstrate that binding to prion protein and prion protein-dependent synaptotoxicity correlate with the presence of a tubular form of amyloid-ß with a defined triple helical structure.
- Andrew J. Nicoll
- , Silvia Panico
- & John Collinge
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Ecscr regulates insulin sensitivity and predisposition to obesity by modulating endothelial cell functions
The transmembrane protein Ecscr has been implicated in the regulation of endothelial cell signalling. Here, the authors show that Ecscr regulates systemic insulin sensitivity and glucose homeostasis in mice by modulating insulin signalling in endothelial cells.
- Yoshiki Akakabe
- , Masahiro Koide
- & Koji Ikeda
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Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome
Consumption of high amounts of glucose leads to the development of insulin resistance and metabolic syndrome. Here, Lanaspa et al.show that the hepatic conversion of glucose into fructose is a key step in the development of glucose-induced metabolic syndrome and fatty liver in mice.
- Miguel A. Lanaspa
- , Takuji Ishimoto
- & Richard J. Johnson
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Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system
Endosomal sorting is regulated by phosphatidylinositol-3-phosphate and anomalies in this process are implicated in Alzheimer’s disease. Here the authors show that deficiency of phosphatidylinositol-3-phosphate in vitroenhances the pathological trafficking and processing of amyloid precursor protein.
- Etienne Morel
- , Zeina Chamoun
- & Gilbert Di Paolo
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Frequency of TERT promoter mutations in human cancers
Reactivation of telomerase has been implicated in human tumorigenesis. Here, somatic mutations in the TERT promoter are reported in cancers of the central nervous system, bladder, follicular cell-derived thyroid and melanoma, thus demonstrating that TERTpromoter mutations are a frequent event in human cancer.
- João Vinagre
- , Ana Almeida
- & Paula Soares
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Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression
The scavenger receptor Scara1, expressed on microglia and macrophages, binds beta amyloid aggregates. In a mouse model of Alzheimer’s disease, the authors show that Scara1deficiency is associated with reduced clearance and increased deposition of aggregates in the brain, which results in early mortality.
- Dan Frenkel
- , Kim Wilkinson
- & Joseph El Khoury
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| Open AccessProthymosin α overexpression contributes to the development of pulmonary emphysema
Pulmonary emphysema obstruct airflow in the lung and often develop in smokers. Here Su et al. show that prothymosin α contributes to emphysema development through alterations in the acetylation of histones and the transcription factor NF-κB, and that exposure to cigarette smoke increases prothymosin α expression.
- Bing-Hua Su
- , Yau-Lin Tseng
- & Chao-Liang Wu
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R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea
Citrobacter rodentiumis an intestinal pathogen of mice widely used to model enteropathogenicE. coli infection in humans. Using a forward genetic approach, Papapietro and colleagues identify R-Spondin 2 expression and resulting Wnt signalling activation as a major regulator of C. rodentium-induced colitis.
- Olivier Papapietro
- , Sarah Teatero
- & Samantha Gruenheid
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Prions disturb post-Golgi trafficking of membrane proteins
Prion protein accumulation in endosomal vesicles has been implicated in the progression of prion diseases. Uchiyama and colleagues infect neuronal cells with prion proteins and find that this delays post-Golgi vesicular trafficking of membrane proteins and impairs insulin signalling.
- Keiji Uchiyama
- , Naomi Muramatsu
- & Suehiro Sakaguchi
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Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer
As cervical tumours become more invasive, levels of episomal human papillomavirus paradoxically tend to decrease. Here the authors identify a network of antiviral and cell cycle genes that is amplified by chromosomal aberrations and promotes cervical tumour progression.
- Karina L. Mine
- , Natalia Shulzhenko
- & Andrey Morgun
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Microbiota-derived lactate accelerates colon epithelial cell turnover in starvation-refed mice
Epithelial cells in the colon mainly use microbial fermentation products as energy sources. Here Okada et al. find that lactate produced by commensal Lactobacillus murinusregulates colonic epithelial cell proliferation and show that mice are more susceptible to carcinogens when refed after a period of starvation.
- Toshihiko Okada
- , Shinji Fukuda
- & Taeko Dohi
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| Open AccessGRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance
The clearance of apoptotic cells by macrophages is important for tissue homoeostasis. Here Nakaya et al. reveal a role for GRK6 in the regulation of apoptotic engulfment and show that GRK6 deficiency in mice leads to autoimmune disease and iron accumulation in the spleen.
- Michio Nakaya
- , Mitsuru Tajima
- & Hitoshi Kurose
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| Open AccessA point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration
Semaphorin 4A is implicated in photoreceptor survival. Nojima and colleagues generate transgenic mice with different mutations in the Sema4A gene and find that point mutation of F350 causes severe degeneration in photoreceptor cells, which can be rescued by virus-mediated gene therapy.
- Satoshi Nojima
- , Toshihiko Toyofuku
- & Atsushi Kumanogoh
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Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration
Heat shock factor-1 is a transcriptional regulator of heat shock proteins that is implicated in neurodegeneration. Kondo and colleagues study the effects of deleting heat shock factor-1 in a mouse model of muscular dystrophy and find that this augments the condition via the accumulation of androgen receptors.
- Naohide Kondo
- , Masahisa Katsuno
- & Gen Sobue
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Elevated oncofoetal miR-17-5p expression regulates colorectal cancer progression by repressing its target gene P130
Tumorigenesis has been likened to a form of cellular reversion to the embryonic state. Ma et al.identify a foetal miRNA as an oncogenic activator of the Wnt/β-catenin pathway in colorectal cancer, whose expression is negatively correlated with survival but is positively correlated with response to adjuvant chemotherapy.
- Yanlei Ma
- , Peng Zhang
- & Huanlong Qin
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A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology
The mislocalization and downregulation of the proteins TDP-43 and ADAR2, respectively, are implicated in amyotrophic lateral sclerosis pathology. Yamashita et al. find that downregulation of ADAR2 results in calcium-permeable AMPA receptor-mediated calpain activation and subsequent aberrant cleavage of TDP-43.
- Takenari Yamashita
- , Takuto Hideyama
- & Shin Kwak
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| Open AccessSymptomatic atherosclerosis is associated with an altered gut metagenome
The gut microbiota has emerged as an environmental factor that can influence the development of obesity and diabetes. Here, Karlsson et al. report compositional and functional alterations of the gut metagenome in patients with symptomatic atherosclerosis.
- Fredrik H. Karlsson
- , Frida Fåk
- & Jens Nielsen
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Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
The ras family of oncogenes consists of H-ras, K-ras and N-ras, and usually only one of these genes is mutated in a given tumour type. In this study, K-ras is found to promote the activation of wild-type H-ras and N-ras in a manner dependent on the Ras guanine nucleotide exchange factor Son of sevenless.
- Hao-Hsuan Jeng
- , Laura J Taylor
- & Dafna Bar-Sagi
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Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology
The protein α-synuclein is implicated in Parkinson's disease. Rhinn and colleagues perform gene expression analysis and find that specific α-synuclein transcripts are preferentially associated with Parkinson's disease, and that they potentiate the accumulation of α-synuclein protein.
- Herve Rhinn
- , Liang Qiang
- & Asa Abeliovich
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| Open AccessEnhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B
HSP70 is a molecular chaperone that aids protein folding. In this study, HSP70 is shown to be methylated and this post-translationally modified protein is elevated in expression in human cancers and promotes the activity of Aurora kinase B.
- Hyun-Soo Cho
- , Tadahiro Shimazu
- & Ryuji Hamamoto
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| Open AccessHigh-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring
Environmental factors can influence one's susceptibility to cancer, but it is not clear whether such an influence extends beyond the directly exposed generations. Here, feeding pregnant rats with a high-fat diet or a hormone derivative, the authors observe increased breast cancer risk in up to three subsequent generations.
- Sonia de Assis
- , Anni Warri
- & Leena Hilakivi-Clarke
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| Open AccessABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer
In mammalian cells, ABC transporter proteins were thought to exclusively export a range of substrates out of cells. Quazi and colleagues show that, in retinal photoreceptor cells, ABCA4 is acting as an importer of phospholipids and that mutations known to cause Stargardt disease decrease its activity.
- Faraz Quazi
- , Stepan Lenevich
- & Robert S. Molday
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SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane
PTEN is a tumour suppressor that inhibits activation of the phosphatidylinositol 3-kinase pathway. These authors show that PTEN is SUMOylated on two lysine residues and that this modification is required for binding to acidic phospholipids and blocking tumour formation in mice.
- Jian Huang
- , Jie Yan
- & Jianxiu Yu
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| Open AccessMelanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment
Exposure to ultraviolet light is responsible for a large proportion of melanomas but the molecular mechanisms are unknown. In this study, melanoma is found to be induced in mice by UVA and UVB light in a pigment-dependent and -independent manner, respectively, resulting in different types of DNA damage.
- Frances P. Noonan
- , M. Raza Zaidi
- & Edward C. De Fabo
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Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation
Inositol polyphosphate 4 phosphatase regulates phosphoinositide signalling and is associated with an increased risk of asthma. Aichet al. show that, in a mouse model of airway inflammation, calpains degrade inositol polyphosphate 4 phosphatase resulting in exacerbated phosphoinositide 3-kinase signalling.
- Jyotirmoi Aich
- , Ulaganathan Mabalirajan
- & Balaram Ghosh
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Differentiation of multipotent vascular stem cells contributes to vascular diseases
De-differentiation and proliferation of vascular smooth muscle cells is thought to have a dominant role in vascular remodelling. Here, Tanget al. identify a new type of multipotent vascular stem cell in the blood vessel wall that contributes to this process, thereby challenging the established hypothesis.
- Zhenyu Tang
- , Aijun Wang
- & Song Li