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| Open AccessGut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here, the authors show in a mice model that insulin action in the gut may play a protective role in the development of NASH and HCC in diabetes.
- Kotaro Soeda
- , Takayoshi Sasako
- & Kohjiro Ueki
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Article
| Open AccessGreen leaf volatile sensory calcium transduction in Arabidopsis
Plants sense volatiles emitted by injured neighboring plants and elicit defense responses to external threats. Here, the authors show that Arabidopsis leaves uptake two green leaf volatiles via stomata and trigger cytosolic Ca2+ defense signaling.
- Yuri Aratani
- , Takuya Uemura
- & Masatsugu Toyota
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Article
| Open AccessO-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations
The neurofilament cytoskeleton is critical for axon function and can be dysregulated in disease. Here, the authors show that intracellular glycosylation regulates a key neurofilament protein.
- Duc T. Huynh
- , Kalina N. Tsolova
- & Michael Boyce
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Article
| Open AccessAndrogen receptor is a determinant of melanoma targeted drug resistance
BRAF inhibitor response in melanoma is variable, and BRAF mutated patients often relapse. Here, the authors show that androgen receptor expression is linked to BRAF inhibitor response, and is a potential therapeutic target to increase efficacy.
- Anastasia Samarkina
- , Markus Kirolos Youssef
- & Gian Paolo Dotto
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Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
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Article
| Open AccessGLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.
- Shane C. Wright
- , Aikaterini Motso
- & Volker M. Lauschke
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Article
| Open AccessLuminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands
Rocha and co-authors show that loss of luminal Rank signaling causes abnormal alveolar differentiation and lactation failure. Subsequent pregnancies activate bipotency in basal cells, replacing unfit luminal cells, and restoring lactation.
- Ana Sofia Rocha
- , Alejandro Collado-Solé
- & Eva González-Suárez
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Article
| Open AccessThe USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6
Wnt receptor levels drive signaling. Here the authors find that precise signaling in the Wnt morphogen gradient relies on Usp46, a deubiquitylase that enhances target cells sensitivity by increasing cell surface levels of the Wnt receptor Arrow/LRP6.
- Zachary T. Spencer
- , Victoria H. Ng
- & Yashi Ahmed
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Article
| Open AccessThe USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling
Wnt receptors are controlled by their ubiquitin-mediated proteolysis. The authors show that the USP46 deubiquitylase complex potentiates Wnt signaling in human cells, Xenopus, and zebrafish by inhibiting cell surface LRP6 degradation.
- Victoria H. Ng
- , Zachary Spencer
- & Ethan Lee
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Article
| Open AccessCytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress
Endonuclease G is known to translocate to the nucleus during apoptosis, but less is known about its role in the cytosol. Here, the authors show that cytoplasmic endonuclease G activates mTORC2 signaling and ER stress to promote NAFLD in female mice.
- Wenjun Wang
- , Junyang Tan
- & Qinghua Zhou
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Article
| Open AccessInterferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Here the authors show that the basal activation of the interferon/ISG15 pathway is required for the stability of nascent DNA during replication and its upregulation promotes viability, proliferation and acquisition of drug resistance in BRCA1/2 deficient cells.
- Ramona N. Moro
- , Uddipta Biswas
- & Lorenza Penengo
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Article
| Open AccessFast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9
Methods for somatic gene perturbation would offer advantages for screening multiple muscle gene candidates. Here the authors couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery and report a system for effective somatic gene deletions in mice.
- Marco Thürkauf
- , Shuo Lin
- & Markus A. Rüegg
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Article
| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessThe TNFR Wengen regulates the FGF pathway by an unconventional mechanism
Mechanistic studies of receptor action have aided our understanding of developmental processes and facilitated drug development. Here they show that the TNFR-Wengen acts by forming a complex with the FGFR-Breathless, regulating its activity during cell differentiation in the developing respiratory system of Drosophila.
- Annalisa Letizia
- , Maria Lluisa Espinàs
- & Marta Llimargas
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Article
| Open AccessRegulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites
The molecular mechanisms responsible for cellular cholesterol distribution remain unclear. Here, the authors identify a key role of lipid transfer proteins ORP9, OSBP, and GRAMD1s in maintaining cholesterol levels in the Golgi and plasma membrane.
- Tomoki Naito
- , Haoning Yang
- & Yasunori Saheki
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Article
| Open AccessFgf signalling triggers an intrinsic mesodermal timer that determines the duration of limb patterning
The limb bud is patterned by crosstalk between the mesoderm and the overlying apical ectodermal ridge, but it has been difficult to determine the requirement for different ligands in this process. Here the authors use a chick wing explant system to show that fibroblast growth factors trigger a mesodermal programme that is key for timing limb bud patterning.
- Sofia Sedas Perez
- , Caitlin McQueen
- & Matthew Towers
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Article
| Open AccessMechanodetection of neighbor plants elicits adaptive leaf movements through calcium dynamics
Pantazopoulou et al. discovered that leaves sense neighbors by mutual touching of hairs on their surface, called trichomes. Using fluorescent biosensors, they show that this triggers a calcium wave to activate leaf movement away from competitors
- Chrysoula K. Pantazopoulou
- , Sara Buti
- & Ronald Pierik
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Article
| Open AccessSer14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice
The anti-apoptotic function of Bcl-xL in the heart is diminished by Mst1-mediated phosphorylation of Serine14. Here, the authors show that the Bcl-xL phosphorylation is also promoted by hemodynamic stress, which plays an essential role in mediating compensatory cardiac hypertrophy and contractility.
- Michinari Nakamura
- , Mariko Aoyagi Keller
- & Junichi Sadoshima
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Article
| Open AccessMonolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification
Generation of primordial germ cell-like cells (PGCLCs) from human pluripotent cells (hPSCs) offers insight into the mechanisms underlying human reproduction, but often requires complex methods. Here they describe a simplified monolayer protocol to differentiate and purify PGCLCs for further analysis.
- Sivakamasundari Vijayakumar
- , Roberta Sala
- & Vittorio Sebastiano
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Article
| Open AccessTime space and single-cell resolved tissue lineage trajectories and laterality of body plan at gastrulation
Gastrulation entails a series of events that are highly coordinated in space and time. Here they construct a spatiotemporal molecular atlas of lineage trajectories in the gastrulating mouse embryo by mapping single cells to spatial coordinates in the germ layers with reference to positional data in the transcriptome.
- Ran Wang
- , Xianfa Yang
- & Naihe Jing
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Article
| Open AccessAlk1 acts in non-endothelial VE-cadherin+ perineurial cells to maintain nerve branching during hair homeostasis
Vascular endothelial (VE)-cadherin is a well-recognized endothelial cell marker. Here, the authors unveil unexpected heterogeneity in the skin VE-cadherin lineage, identifying a dynamic, non-endothelial VE-cadherin+ perineurial cell population.
- Gopal Chovatiya
- , Kefei Nina Li
- & Tudorita Tumbar
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Article
| Open AccessHuman blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity
The microvasculature is critical for delivery of oxygen and metabolites throughout tissues. Here they use human blood vessel organoids to show that CTGF is a critical paracrine regulator of microvascular integrity that can restore pericyte coverage and vessel structure.
- Sara G. Romeo
- , Ilaria Secco
- & Anna Zampetaki
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Article
| Open AccessCyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Spatial compartmentalization is central to nuclear function. Here, the authors demonstrate that EPAC1 can enter the nucleus and regulate the transcription of a histone cluster by forming biomolecular condensates in its proximity in response to cAMP.
- Liliana Felicia Iannucci
- , Anna Maria D’Erchia
- & Konstantinos Lefkimmiatis
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Article
| Open AccessActivation of the integrated stress response by inhibitors of its kinases
The integrated stress response (ISR) is the focus of numerous investigations and drug development programs. Here, the authors show that ATP-competitive inhibitors of ISR kinases PERK, PKR and GCN2 inhibit their targets but activate the ISR by directly binding to and activating a sister ISR kinase.
- Maria Szaruga
- , Dino A. Janssen
- & Anne Bertolotti
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Article
| Open AccessSerotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages
Serotonin signaling is well known for modulating animal behavior. Here the authors discovered it plays a developmental role in regulating actomyosin contractility driven cellular mechanics and tissue flows during gastrulation of insect and bird.
- Sanjay Karki
- , Mehdi Saadaoui
- & Thomas Lecuit
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Article
| Open AccessAstrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels
Neuroinflammation is a common feature of many neurological disorders. Here, the authors show that the Orai1 calcium channel functions as a signaling hub in astrocytes to control astrocyte-driven brain inflammation and inflammation-induced depression-like behaviors in mice.
- Michaela M. Novakovic
- , Kirill S. Korshunov
- & Murali Prakriya
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Article
| Open AccessAryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Dietary zinc and plant-derived aryl hydrocarbon receptor (AHR) agonists are involved in maintaining intestinal epithelium integrity. The authors show that combined supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.
- Xiuchuan (Lucas) Hu
- , Wenfeng Xiao
- & Christer Hogstrand
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Article
| Open AccessLrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis
Regulatory T cells, and to certain extent other T cell subsets, limit the immune response to avoid harmful inflammation and tissue damage. Here authors identify a surface molecule, Lrig1, that is directly responsible for the suppressive function in regulatory T cells and in Il-17-producing helper T cells.
- Jae-Seung Moon
- , Chun-Chang Ho
- & Sang-Kyou Lee
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Article
| Open AccessCENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly
It is unknown how the kinetochore fibrous corona is disassembled. Here, the authors reveal that Aurora A and B kinases-mediated phosphorylation activates CENP-E, which is essential to prevent the premature removal of corona proteins by dynein.
- Susana Eibes
- , Girish Rajendraprasad
- & Marin Barisic
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Article
| Open AccessNacα protects the larval fat body from cell death by maintaining cellular proteostasis in Drosophila
Protein homeostasis is crucial for maintaining cellular homeostasis. Here, the authors show that proteotoxic stress caused by Nacalpha mutants specifically and progressively induces cell death in the apoptosis-resistant Drosophila larval fat body.
- Takayuki Yamada
- , Yuto Yoshinari
- & Takashi Nishimura
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Article
| Open AccessLoss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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Article
| Open AccessNeuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling
A-kinase anchoring proteins (AKAPs) target protein kinase A to specific locations within the cell. Here, the authors identify SPHKAP as an AKAP that enriches protein kinase A near ER-plasma membrane contact sites in brain neurons.
- Nicholas C. Vierra
- , Luisa Ribeiro-Silva
- & James S. Trimmer
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Article
| Open AccessPINK1 and Parkin regulate IP3R-mediated ER calcium release
Loss of two PD genes, PINK1 and Parkin, leads to a robust increase in ER calcium release. Here, the authors show that suppression of IP3R activity via inhibiting CISD1 is sufficient to rescue the PD-related phenotypes in PINK1 or Parkin null animal models.
- Su Jin Ham
- , Heesuk Yoo
- & Jongkyeong Chung
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Article
| Open AccessTIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation
CD226 provides a co-stimulatory signal to the T cell receptor during activation, and TIGIT is believed to inhibit this process by competing for the CD226 ligand CD155. Here authors show that ligand binding induces dense nanocluster formation by TIGIT which initiates intrinsic, CD226 independent inhibitory signals, proximal to T cell receptor signalling.
- Jonathan D. Worboys
- , Katherine N. Vowell
- & Daniel M. Davis
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Article
| Open AccessEndothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Estrogen has anti-diabetic effects via estrogen receptor alpha (ERα). Here, authors show that via coupled nuclear and non-nuclear actions, ERα in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.
- Anastasia Sacharidou
- , Ken Chambliss
- & Philip W. Shaul
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Article
| Open AccessIntegrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis
Zhang et al. show that the adhesion receptor integrin β3 directly inhibits G protein mediated RhoA activation and granule secretion. A peptide mimicking this effect selectively inhibits platelet secretion but not integrin-mediated platelet adhesion.
- Yaping Zhang
- , Xiaojuan Zhao
- & Xiaoping Du
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Article
| Open AccessSpinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer
Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.
- Valentina Cigliola
- , Adam Shoffner
- & Kenneth D. Poss
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Article
| Open AccessMTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis
MTH1 hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Here, the authors show that MTH1 is expressed in platelets and its deficiency increases mitochondrial DNA oxidative damage, impairs platelet function and hemostasis.
- Yangyang Ding
- , Xiang Gui
- & Jianlin Qiao
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Article
| Open AccessA HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Cholesterol synthesis is highly oxygen consuming but how it is regulated by oxygen levels has not been clear. Here, Dickson et al. identify a HIF-independent, oxygen-sensing pathway for controlling cholesterol synthesis in human cells involving hypoxic-mediated degradation of SREBP2.
- Anna S. Dickson
- , Tekle Pauzaite
- & James A. Nathan
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Article
| Open AccessPathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations
Signaling pathway selectivity downstream of GPCRs is not fully understood. Here, authors perform functional analysis of Frizzled mutants to uncover state-stabilizing residues or ‘micro-switches’ mediating selectivity towards Disheveled over G proteins.
- Lukas Grätz
- , Maria Kowalski-Jahn
- & Gunnar Schulte
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Article
| Open AccessModulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging
The extent of phosphorylated p38 MAPK is known to determine signaling. Here, the authors show the relative pool of non-phosphorylated p38 MAPK modulates signaling output to control growth, lysosome formation and neuronal integrity during early aging.
- Wang Yuan
- , Yi M. Weaver
- & Benjamin P. Weaver
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Article
| Open AccessCircular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
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Article
| Open AccessMacrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice
Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.
- Liming Yu
- , Lin Xu
- & Philip W. Shaul
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Article
| Open AccessHighly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi
Stretch-activated ion channel Piezo1 contribures to mechanotransduction in many tissues, but its output is mostly measured indirectly. Here, the authors introduce GenEPi, a fluorescent reporter for directly visualizing Piezo1 activation-dependent calcium influx.
- Sine Yaganoglu
- , Konstantinos Kalyviotis
- & Periklis Pantazis
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Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
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Article
| Open AccessLysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization
Cystinosis is a lysosomal storage disease that affects the kidney. Here, the authors use preclinical models and advanced profiling techniques to discover the mechanism by which defective cystine mobilization from lysosomes disrupts kidney cell function, offering insights into potential therapies.
- Marine Berquez
- , Zhiyong Chen
- & Alessandro Luciani
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Article
| Open AccessReprogramming of the transcriptome after heat stress mediates heat hormesis in Caenorhabditis elegans
Xu and colleagues report that the poly-U-specific endoribonuclease ENDU-2/ENDOU activates a transcriptional reprogramming after a brief heat shock and this has a long-term beneficial effect in the model organism C. elegans.
- Fan Xu
- , Ruoyao Li
- & Wenjing Qi
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Article
| Open AccessDeciphering intercellular signaling complexes by interaction-guided chemical proteomics
Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.
- Jiangnan Zheng
- , Zhendong Zheng
- & Ruijun Tian
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Comment
| Open AccessLimited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies
Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.
- Sara Weirich
- & Albert Jeltsch