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| Open AccessDissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium
Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft-like progenitor for pulmonary neuroendocrine cells and ionocytes.
- Katherine C. Goldfarbmuren
- , Nathan D. Jackson
- & Max A. Seibold
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Article
| Open AccessHepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis
Progressive fibrosis is a driver of morbidity and mortality in many chronic liver diseases, but the underlying mechanisms are incompletely understood. Here, the authors show that mitochondria-derived damage-associated molecular patterns are released from injured hepatocytes and can trigger fibrogenic activation of hepatic stellate cells.
- Ping An
- , Lin-Lin Wei
- & Yury V. Popov
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Article
| Open AccessPhagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity
Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.
- Samuel M. Gonçalves
- , Cláudio Duarte-Oliveira
- & Agostinho Carvalho
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Article
| Open AccessSingle-cell transcriptional networks in differentiating preadipocytes suggest drivers associated with tissue heterogeneity
The origin of the heterogeneity of metabolic and inflammatory profiles exhibited by white adipocytes is little understood. Here, using scRNA-seq and computational methods, the authors show that differentiating preadipocytes exhibit gene expression differences and suggest underlying regulators.
- Alfred K. Ramirez
- , Simon N. Dankel
- & Simon Kasif
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Article
| Open AccessThe UPR sensor IRE1α and the adenovirus E3-19K glycoprotein sustain persistent and lytic infections
Adenovirus (AdV) can cause persistent infections, but underlying mechanisms are poorly understood. Here, Prasad et al. show that the AdV glycoprotein E3-19K activates the unfolded protein response sensor IRE1α, and that this triggers a feedforward loop that sustains persistent infection in the presence of interferon.
- Vibhu Prasad
- , Maarit Suomalainen
- & Urs F. Greber
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Article
| Open AccessParacrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes
Glucagon is elevated Type-2 diabetes, which contributes to poor glucose control in patients with the disease. Here the authors report that secretion of the hormone is controlled by paracrine inhibition, and that resistance of α-cells to somatostatin can explain hyperglucagonemia in type-2 diabetes.
- Muhmmad Omar-Hmeadi
- , Per-Eric Lund
- & Sebastian Barg
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Article
| Open AccessA signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size
Insulin receptor signaling governs central physiological functions related to cell growth and metabolism. Here the authors use protein complex purification and super-resolution microscopy to show that insulin receptor activity requires association with dystrophin glycoprotein complex and plakoglobin.
- Yara Eid Mutlak
- , Dina Aweida
- & Shenhav Cohen
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Article
| Open AccessMitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Small open reading frame-encoded peptides (SEPs), shorter than 100 amino acids, are involved in many cell biological processes. Here the authors identify 16 nuclear-encoded mitochondrial SEPs, including BRAWNIN, an essential regulator of respiratory chain complex III assembly and ATP production.
- Shan Zhang
- , Boris Reljić
- & Lena Ho
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Article
| Open AccessHaploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism
The transcription factor SREBP is a well-studied and major regulator of sterol and fatty acid metabolism. Here, the authors used haploid genetic screens to identify the Golgi-resident protein SPRING as a new modulator of SREBP by regulating the level of functional SREBP cleavage-activating protein (SCAP).
- Anke Loregger
- , Matthijs Raaben
- & Noam Zelcer
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Article
| Open AccessCerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17
It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons.
- Qiong Liu
- , Shanshan Huang
- & Shihua Li
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Article
| Open AccessImpaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.
- Alessandro Luciani
- , Anke Schumann
- & Olivier Devuyst
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| Open AccessThe tight junction protein TJP1 regulates the feeding-modulated hepatic circadian clock
The circadian clock regulates rhythms of physiology and metabolism in response to environmental cues such as food intake. Here, the authors show that tight junction protein 1 (TJP1) interacts with period 1 and modulates its nuclear translocation in a mTOR-dependent manner.
- Yi Liu
- , Yuanyuan Zhang
- & Yiguo Wang
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Article
| Open AccessAndrogen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer
SPINK1 upregulation is found in ~10–25% of prostate cancers. Here, they show that whilst SPINK1 is transcriptionally repressed by androgen receptor and its co-repressor REST, it is upregulated after androgen-deprivation therapy, which leads to neuroendocrine differentiation of prostate cancer cells.
- Ritika Tiwari
- , Nishat Manzar
- & Bushra Ateeq
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Article
| Open AccessMelanoblast transcriptome analysis reveals pathways promoting melanoma metastasis
Metastatic cells can mimic many of the phenotypic behaviors of embryonic cells. Here, the authors generate a melanoblast-specific transcriptome using a genetically engineered mouse model and identify KDELR3 as a pro-metastasis gene in melanoma.
- Kerrie L. Marie
- , Antonella Sassano
- & Pravin J. Mishra
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Article
| Open AccessIrp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification
Iron metabolism is linked to type 2 diabetes. Here the authors describe a mechanism through which cellular iron deficiency caused by loss of Irp2 impairs Cdkal1 function, resulting in inaccurate proinsulin translation, impaired proinsulin processing and reduced insulin secretion.
- Maria C. Ferreira dos Santos
- , Cole P. Anderson
- & Elizabeth A. Leibold
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Article
| Open AccessPHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase
mTORC1 is an important regulator of muscle mass. Here, the authors show that the PHD1 controls muscle mass in a hydroxylation-independent manner. PHD1 prevents the degradation of leucine sensor LRS during oxygen and amino acid depletion to ensure effective mTORC1 activation in response to leucine.
- Gommaar D’Hulst
- , Inés Soro-Arnaiz
- & Katrien De Bock
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Article
| Open AccessSensing of HIV-1 by TLR8 activates human T cells and reverses latency
Manipulation of Toll-like receptors (TLRs) affects HIV-1 infection and latency reversal. Here, the authors show that HIV-1 is endocytosed and recognized by TLR8 in human primary CD4+T cells and that TLR8 stimulation induces an inflammatory response that promotes HIV-1 replication and reversal of latency.
- Hany Zekaria Meås
- , Markus Haug
- & Trude Helen Flo
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Article
| Open AccessA truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice
UVRAG is involved in autophagy, which loses its tumour suppressor functions when in its truncated form in cancers. Here, the authors use a mouse model that inducibly express this truncated protein and show impaired autophagy, enhanced inflammation and β-catenin stabilisation, which promotes spontaneous tumorigenesis.
- Christine Quach
- , Ying Song
- & Chengyu Liang
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Article
| Open AccessMonkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease
Most cases of autosomal dominant polycystic kidney disease (ADPKD) are due to mutations in PKD1. Here, Tsukiyama et al. generate monkeys with mutations in PKD1 and show that animals recapitulate key pathological features of the human disease, suggesting these may provide insights into ADPKD pathogenesis and contribute to the development of future therapeutic strategies.
- Tomoyuki Tsukiyama
- , Kenichi Kobayashi
- & Masatsugu Ema
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Article
| Open AccessCSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence
Senescence of metabolically active cells is a process linked to ageing. Here the authors reveal that CSB is required to block replicative senescence, and epigenetic control of CSB downregulation triggers proliferative arrest in a p21-dependent manner.
- Clément Crochemore
- , Cristina Fernández-Molina
- & Miria Ricchetti
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Article
| Open AccessA cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion
Pre-malignant cells harbouring oncogenic mutations can populate and spread throughout a tissue. Here, using a rainbow mouse system, the authors explore how clonal expansion in the mouse intestine might explain high levels of intra-tumoural heterogeneity observed in the disease.
- Peter G. Boone
- , Lauren K. Rochelle
- & Joshua C. Snyder
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Article
| Open AccessQuantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process
How epigenetics coordinate with genetics to impact protein fitness is unknown. Here, using a Variation Spatial Profiling strategy and machine learning, the authors map HDAC impact on a full set of Niemann pick C1 disease variants to quantitate an unanticipated plasticity in central dogma.
- Chao Wang
- , Samantha M. Scott
- & William E. Balch
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Article
| Open AccessNeratinib protects pancreatic beta cells in diabetes
Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.
- Amin Ardestani
- , Sijia Li
- & Kathrin Maedler
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Article
| Open AccessThe tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner
TMEM127 is a tumor suppressor protein, loss of which predisposes to catecholamine-secreting tumors. Here the authors show that TMEM127 expression is modulated by nutritional status and that it has a role in regulating organismal insulin sensitivity.
- Subramanya Srikantan
- , Yilun Deng
- & Patricia L. M. Dahia
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Article
| Open AccessEmbryonic mesothelial-derived hepatic lineage of quiescent and heterogenous scar-orchestrating cells defined but suppressed by WT1
Activated hepatic stellate cells of putative mesodermal origin orchestrate scarring during injury. Here, the authors define a discrete morphologically plastic lineage of embryonic mesothelial-derived scar-orchestrating cells, through a distinct quiescent adult precursor, defined and paradoxically inhibited by WT1.
- Timothy James Kendall
- , Catherine Mary Duff
- & Nicholas Dixon Hastie
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Article
| Open AccessTFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes
Mutations in the gene HADHA result in mitochondrial tri-functional protein (MTP) deficiency and can result in sudden infant death syndrome for which there is no treatment. Here the authors show that the MTP deficient pathology in human cardiomyocytes leads to an abnormal cardiolipin pattern and suggests that cardiolipin affecting compounds may serve as a potential therapy.
- Jason W. Miklas
- , Elisa Clark
- & Hannele Ruohola-Baker
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Article
| Open AccessArctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes
Arctigenin (ATG) is the major active component of a Chinese herbal remedy known to reduce proteinuria in patients with diabetic kidney disease (DKD). Here, Zhong et al. identify PP2A as a pharmacological target of ATG in podocytes, and find that PP2A is responsible for some of the beneficial effects of ATG in mouse models of DKD.
- Yifei Zhong
- , Kyung Lee
- & Ruijie Liu
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Article
| Open AccessZika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells
Zika virus (ZIKV) can infect the central nervous system, but it is not clear how it reaches the brain. Here, Ayala-Nunez et al. show in ex vivo and in vivo models that ZIKV can hitch a ride in monocytes in a Trojan Horse manner to cross the endothelium and disseminate the virus.
- Nilda Vanesa Ayala-Nunez
- , Gautier Follain
- & Raphael Gaudin
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Article
| Open AccessTFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths
TFF3 secretion by goblet cells regulates mucus viscosity and wound healing, but a receptor for TFF3 has not been identified. Here, the authors show that TFF3 binds LINGO2 to de-repress and enhance EGFR signaling that drives wound healing and immunity against helminths.
- Nicole Maloney Belle
- , Yingbiao Ji
- & De’Broski R. Herbert
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Article
| Open AccessIdentification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer
The identification of synthetic essential genes of PTEN is of therapeutic potential for PTEN-deficient prostate cancers. Here, the authors show that ARID4B is a synthetic essential gene in these cancers in which deficiency of PTEN prompts the AKT-ARID4B feedback loop required for activation of the PI3K-AKT signaling pathway.
- Ray-Chang Wu
- , In-Chi Young
- & Mei-Yi Wu
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Article
| Open AccessInactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction
Elevated glucagon level in obesity and diabetes promotes hepatic glucose production and hyperglycemia. Here the authors report that NF-κB2 augments the hepatic glucagon responses by inhibiting PDE4B induction, and that metformin lowers blood glucose in part by inhibiting NF-κB2.
- Wen-Song Zhang
- , An Pan
- & Ping Li
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Article
| Open AccessNeural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis
Stress kinases are activated in peripheral ischemic tissues in the presence of vascular diseases. Here the authors show that inhibition of the neural JNK3 kinase improves recovery from hind limb ischemia in animals through activation of the transcription factors Egr1/Creb1 and upregulation of growth factors.
- Shashi Kant
- , Siobhan M. Craige
- & John F. Keaney Jr.
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Article
| Open AccessThe mutational landscape of a prion-like domain
TDP43 aggregates are a hallmark of amyotrophic lateral sclerosis. By using deep mutagenesis to measure the toxicity of more than 50,000 mutations in the prion domain of TDP43, the authors conclude that mutations that increase toxicity promote formation of liquid-like condensates, while aggregation of TDP43 is protective for the cell.
- Benedetta Bolognesi
- , Andre J. Faure
- & Ben Lehner
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Article
| Open AccessSingle-cell transcriptomics reveals multi-step adaptations to endocrine therapy
The development of resistance to endocrine therapy is a significant, clinical problem in breast cancer. Here, the authors identify a rare subpopulation of cells that drive resistance following transcriptional reprogramming.
- Sung Pil Hong
- , Thalia E. Chan
- & Luca Magnani
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Article
| Open AccessReplication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
Mismatch repair (MMR)-deficient cancers are characterized by microsatellite instability (MSI) and hypermutation. Here authors reveal a mechanism by which replication stress induces MSI and associated induction of mutations in vitro.
- Yusuke Matsuno
- , Yuko Atsumi
- & Ken-ichi Yoshioka
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Article
| Open AccessGenetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements
Here, the authors show that reticulocytes derived from immortalized erythroblasts support invasion and development of Plasmodium falciparum and use CRISPR-mediated gene knockout and complementation of an invasion receptor to demonstrate utility of this model system for research in malaria invasion.
- Timothy J. Satchwell
- , Katherine E. Wright
- & Jake Baum
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Article
| Open AccessMYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat
Genes related to lysosomal and autophagic systems are transcriptionally regulated by the Mit/TFE family of transcription factors. Here the authors show that MYC, in association with HDACs, suppresses the expression of lysosomal and autophagy genes by competing with the Mit/TFE transcription factors for occupancy of their target gene promoters.
- Ida Annunziata
- , Diantha van de Vlekkert
- & Alessandra d’Azzo
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Article
| Open AccessTonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging
Activation of thermogenic beige adipocytes within white adipose tissue increases energy expenditure. Here, the authors show that expression of TonEBP in adipocytes is increased when mice are fed a high fat diet and that it suppresses expression of beta3-adrenoreceptor.
- Hwan Hee Lee
- , Seung Min An
- & Hyug Moo Kwon
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Article
| Open AccessPolarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity
Many developing tissues require Par-driven polarization, but its role in mammalian tissue maintenance is unclear. Here, the authors show that in mouse epidermis, Par3 governs tissue homeostasis not via orientation of cell division but by coupling cell mechanics with mitotic accuracy and genome integrity.
- Martim Dias Gomes
- , Soriba Letzian
- & Sandra Iden
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Article
| Open AccessThe tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression
In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.
- Hélène Lazareth
- , Carole Henique
- & Pierre-Louis Tharaux
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Article
| Open AccessSingle-cell reconstruction of follicular remodeling in the human adult ovary
In the ovary, follicular degeneration occurs after folliculogenesis, with one dominant follicle reaching maturity every month. Here, by performing single cell RNA-seq of adult human follicles, the authors identify subclasses of granulosa and theca cell lineages, which correlate with the growth or degeneration of the follicles.
- X. Fan
- , M. Bialecka
- & S. M. Chuva de Sousa Lopes
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Article
| Open AccessEndothelial cell clonal expansion in the development of cerebral cavernous malformations
Cerebral cavernous malformation is a vascular disease characterized by capillary-venous cavernomas in the central nervous system. Here the authors show that cavernomas display benign tumor characteristics and originate from the clonal expansion of mutated endothelial progenitors which can attract surrounding wild-type cells, inducing their mesenchymal transition and leading to growth of the cavernoma.
- Matteo Malinverno
- , Claudio Maderna
- & Elisabetta Dejana
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Article
| Open AccessTime-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption
Time-restricted feeding (TRF) has beneficial metabolic effects. Here the authors examine how TRF impacts muscle physiology using fly models of metabolically adverse conditions, including diet and genetic models of obesity as well as circadian rhythm disruption, and find that TRF ameliorates skeletal muscle dysfunction.
- Jesús E. Villanueva
- , Christopher Livelo
- & Girish C. Melkani
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Article
| Open AccessTargeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.
- Charles C. Bell
- , Katie A. Fennell
- & Mark A. Dawson
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Article
| Open AccessIAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function
Type 2 diabetes is associated with islet amyloid deposits derived from islet amyloid polypeptide (IAPP) expressed by β-cells. Here the authors show that IAPP misfolded protein stress induces the hypoxia inducible factor 1 alpha injury repair pathway and activates survival metabolic changes mediated by PFKFB3.
- Chiara Montemurro
- , Hiroshi Nomoto
- & Slavica Tudzarova
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Article
| Open AccessTranslatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells
The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.
- Kim R. Kampen
- , Laura Fancello
- & Kim De Keersmaecker
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Article
| Open AccessThe K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy
Mutation of LMNA, encoding Lamin A/C nuclear proteins, cause dilated cardiomyopathy and conduction disorders. Here, the authors show that patient-specific iPSC-derived CMs carrying the K219T LMNA mutation have downregulated Nav1.5 channels due to dynamic cooperation of Lamin A/C and Polycomb repressor complex 2 at the SCN5A promoter.
- Nicolò Salvarani
- , Silvia Crasto
- & Elisa Di Pasquale
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Article
| Open AccessSREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer
ERα breast cancer can relapse to metastatic disease following endocrine therapy. Here, the authors find that when aromatase inhibitor treatment resistance develops, epigenomic reprogramming drives Keratin-80 upregulation via SREBP1, and promotes cytoskeletal rearrangements that drive cancer cell invasion.
- Ylenia Perone
- , Aaron J. Farrugia
- & Luca Magnani
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Article
| Open AccessMolecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote
Box jellyfish venom causes tissue damage, pain, and death through unknown molecular mechanisms. Here, Lau et al. perform a CRISPR screen to identify genes required for venom action and use this information to develop an antidote that blocks venom-induced pain and tissue damage in vivo.
- Man-Tat Lau
- , John Manion
- & G. Gregory Neely