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| Open AccessCells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)
Cells experience various osmotic perturbation, but cellular osmosensing mechanisms remain obscure. Here, the authors report that cells recognize osmotic stress from the inside through macromolecular crowding-driven and poly(ADP-ribose)-conditioned liquid–liquid phase separation.
- Kengo Watanabe
- , Kazuhiro Morishita
- & Hidenori Ichijo
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Article
| Open AccessFacilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors
Mutations in ENT3, encoded by SLC29A3, result in anaemia and erythroid hypoplasia, suggesting roles in erythropoiesis. Here the authors show that ENT3 acts as a lysosomal bile acid transporter, and mutation compromises taurine conjugated bile acid transport in erythroid progenitors leading to ER stress, and anaemia.
- Avinash K. Persaud
- , Sreenath Nair
- & Rajgopal Govindarajan
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Article
| Open AccessCellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification
Neural stem and progenitor cells (NSPCs) encounter constant stresses during aging, such as elevated oxidative stress. Here the authors show that oxidative stress induced reduction in NSPC neural differentiation is mediated by a FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signalling cascade initiated by FOXO3 oxidation.
- Inah Hwang
- , Hiroki Uchida
- & Jihye Paik
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Article
| Open AccessActivation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands
The RNase activity of Inositol-Requiring Enzyme 1 (IRE1) can be allosterically regulated by ATP-competitive inhibitors of the IRE1 kinase domain. Here, the authors identify ATP-competitive IRE1 RNase activators with improved selectivity and cellular activity, and elucidate their mechanism of action.
- Elena Ferri
- , Adrien Le Thomas
- & Weiru Wang
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Article
| Open AccessProteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response
Protein O-GlcNAcylation is involved in regulating gene expression and maintaining cellular homeostasis. Here, the authors develop a chemical reporter-based strategy for the proteomic profiling and genome-wide mapping of genotoxic stress-induced O-GlcNAcylated chromatin-associated proteins.
- Yubo Liu
- , Qiushi Chen
- & Jianing Zhang
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Article
| Open AccessAkt1 and dCIZ1 promote cell survival from apoptotic caspase activation during regeneration and oncogenic overgrowth
Although executioner caspase activation is considered terminal, some cells are capable of survival, suggesting additional regulation. Here, the authors show that cells in the Drosophila wing imaginal disc survive caspase activation via Akt1 and dCIZ1 and actively participate in tissue regeneration.
- Gongping Sun
- , Xun Austin Ding
- & Denise J. Montell
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Article
| Open AccessThe nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp
Nucleotides pppGpp and ppGpp regulate bacterial responses to nutritional and other stresses, while the potential roles of the related pGpp are unclear. Here, Yang et al. systematically identify proteins interacting with these nucleotides in Bacillus, and show that pGpp has roles distinct from those of (p)ppGpp.
- Jin Yang
- , Brent W. Anderson
- & Jue D. Wang
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Article
| Open AccessTranslational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR
Translation of ATF4 mRNA is stimulated during the integrated stress response. Here the authors show that two noncanonical translation initiation factors eIF2D and DENR are required for translational induction of ATF4 mRNA in Drosophila and human cells.
- Deepika Vasudevan
- , Sarah D. Neuman
- & Hyung Don Ryoo
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Article
| Open AccessDENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4
Upon stress, translation of ATF4 is induced by reinitiating ribosomes following translation of short upstream open reading frames (uORFs). Here the authors show that translation re-initiation of ATF4 is mediated by the DENR-MCTS1 complex which acts on uORFs containing certain penultimate codons.
- Jonathan Bohlen
- , Liza Harbrecht
- & Aurelio A. Teleman
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Article
| Open AccessBasement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue
The molecular mechanisms regulating macrophage recruitment to tumors are unclear. Here, the authors use a Drosophila overgrowth model to show how damaged basement membranes recruit macrophages to undead tissue, via an interdependent effect of reactive oxygen species and matrix metalloproteinase 2.
- Neha Diwanji
- & Andreas Bergmann
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Article
| Open AccessSingle-particle imaging of stress-promoters induction reveals the interplay between MAPK signaling, chromatin and transcription factors
Mitogen-Activated Protein Kinases integrate extracellular information in all eukaryotic cells. Using a live mRNA reporter, here the authors monitor transcriptional bursting in Saccharomyces cerevisiae upon hyper-osmotic shock and characterize the influence of MAPK signalling, chromatin and transcription factors on the dynamics of transcription.
- Victoria Wosika
- & Serge Pelet
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Article
| Open AccessSIRT1 accelerates the progression of activity-based anorexia
Anorexia nervosa is an eating disorder characterized by fear of gaining weight that can lead to serious complications. Here the authors show that inhibition of SIRT1 is protective against the onset and progression of anorectic behavior in an activity-based anorexia model, suggesting SIRT1 could be a potential therapeutic target.
- Timothy M. Robinette
- , Justin W. Nicholatos
- & Sergiy Libert
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Article
| Open AccessTranslational control of breast cancer plasticity
Protein synthesis suppression protects breast cancer cells from clinically relevant stresses like hypoxia. Here, the authors show that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance.
- Michael Jewer
- , Laura Lee
- & Lynne-Marie Postovit
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Article
| Open AccessGenotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
IRE1α plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1α is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.
- Estefanie Dufey
- , José Manuel Bravo-San Pedro
- & Claudio Hetz
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Article
| Open AccessPharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response
Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.
- Magdalena M. Szewczyk
- , Yoshinori Ishikawa
- & Dalia Barsyte-Lovejoy
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Article
| Open AccessNaked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties
Naked mole rats are the longest-lived rodents and produce very-high-molecular-mass hyaluronan (vHMM-HA). Here the authors show that naked mole rat vHMM-HA is better at protecting mouse and human cells from cell cycle arrest and cell death, compared to the high-molecular-mass hyaluronan produced by these species.
- Masaki Takasugi
- , Denis Firsanov
- & Vera Gorbunova
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Article
| Open AccessA kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury
Protein kinases have emerged as critical regulators of disease pathogenesis. Here, the authors have utilized kinome-wide screening approaches to reveal a pathogenic role of CDKL5 kinase in acute kidney injury, which is dependent on suppression of a SOX9-associated transcriptional network.
- Ji Young Kim
- , Yuntao Bai
- & Navjot Singh Pabla
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Article
| Open AccessPharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy
Inhibition of PERK, an endoplasmic reticulum (ER) unfolded protein response (UPR) protein, is a potential pharmacological target for cancer treatment. Here, the authors show that inhibition of PERK under ER stress affects trafficking from the ER to the surface of several key receptor tyrosine kinases, suggesting a selective ER retention.
- Mohamed Mahameed
- , Shatha Boukeileh
- & Boaz Tirosh
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Article
| Open AccessLATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function
The autophagic and Hippo pathways are both well characterized contributors to cancer. Here, Tang et al show that LATS1, but not LATS2, negatively regulates autophagy by promoting Beclin1 ubiquitination, which restricts lethal autophagy induced by sorafenib treatment in cancer cells.
- Fengyuan Tang
- , Ruize Gao
- & Gerhard Christofori
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Article
| Open AccessESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress
The ER increases in size upon stress in response to the UPR and is remodelled after the stressor is removed by a process called recov-ER-phagy. Here, the authors show remodelling to pre-stress ER size occurs by micro-ER-phagy requiring ESCRT-III components CHMP4B and VPS4A.
- Marisa Loi
- , Andrea Raimondi
- & Maurizio Molinari
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Article
| Open AccessNestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop
Loss of Nestin sensitizes non-small cell lung carcinoma (NSCLC) to oxidative stress. Here, the authors report a feedback loop between Nestin and Nrf2 wherein Nestin competes with Nrf2 for Keap1 binding, preventing Nrf2 degradation, and show the Nestin–Keap1–Nrf2 axis to regulate redox homeostasis in NSCLC.
- Jiancheng Wang
- , Qiying Lu
- & Andy Peng Xiang
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Article
| Open AccessSecond messenger Ap4A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells
The second messenger Ap4A contributes to mast cell activation by interacting with HINT1 but the molecular mechanism is not fully understood. Here, the authors show that Ap4A regulates downstream signaling by polymerizing HINT1 and provide insights into how specificity over other second messengers is achieved.
- Jing Yu
- , Zaizhou Liu
- & Jing Wang
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Article
| Open AccessMonitoring cytosolic H2O2 fluctuations arising from altered plasma membrane gradients or from mitochondrial activity
Reliable methods of measuring intracellular H2O2 fluctuations are necessary to advance redox biology. Here the authors design a H2O2 sensor based on the fission yeast peroxiredoxin Tpx1 to sense nanomolar fluctuations of intracellular H2O2 in response to genetic and environmental perturbations.
- Mercè Carmona
- , Laura de Cubas
- & Elena Hidalgo
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Article
| Open AccessDamage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut
Epithelia are exposed to diverse types of environmental stress, but the mechanisms by which epithelial cells sense stress are not well understood. Here, the authors show that a Nox-ROS-Ask1-MKK3-p38 signaling axis integrates various types of stress to promote intestinal regeneration.
- Parthive H. Patel
- , Clothilde Pénalva
- & Bruce A. Edgar
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Article
| Open AccessGenotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis
It is known that genotoxic stress induces high levels of ROS and deplete cellular glutathione stores. Here, Cao et al. uncover a β-catenin-dependent TCF/LEF-independent mechanism that promotes histone-mediated transcriptional activation of glutathione synthesis.
- Lixue Cao
- , Geyan Wu
- & Jun Li
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Article
| Open AccessHSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine
Cells respond to heat shock with transcriptional and translational adaptations but how HSP90 inhibition alters the heat shock proteome is largely unclear. Here, the authors analyze proteome changes upon HSP90 inhibition and show that an m6A-mediated mechanism contributes to the heat shock-induced upregulation of DNAJB4.
- Weili Miao
- , Lin Li
- & Yinsheng Wang
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Article
| Open AccessIdentification of intracellular cavin target proteins reveals cavin-PP1alpha interactions regulate apoptosis
Caveolae are plasma membrane invaginations containing cavin proteins that are disrupted upon stress stimuli, causing cavin release inside the cell. Here, McMahon et al. identify cavin interacting proteins using proteomic analyses and reveal functions in stress signaling that can promote apoptosis.
- Kerrie-Ann McMahon
- , Yeping Wu
- & Robert G. Parton
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Article
| Open AccessPRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway
Cancer cells utilise the unfolded protein response (UPR) to adapt to environmental and ER stress. Here, the authors show that the glycosidase II beta subunit, PRKSCH, protects cancer cells from ER stress, by interacting with IRE1α and activating the IRE1α-XBP1 branch of the UPR.
- Gu-Choul Shin
- , Sung Ung Moon
- & Kyun-Hwan Kim
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Article
| Open AccessThe longevity-promoting factor, TCER-1, widely represses stress resistance and innate immunity
Resistance to stress is often associated with increased longevity. Using the model organism C. elegans the authors here show that TCER-1 enhances lifespan while at the same time increasing sensitivity to a number of biotic and abiotic stressors.
- Francis R. G. Amrit
- , Nikki Naim
- & Arjumand Ghazi
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Article
| Open AccessDNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response
In the Fanconi anemia pathway, deubiquitination of FANCD2 is a fundamental regulatory step. Here, the authors have developed a set of biochemical tools to reconstitute FANCD2 deubiquitination by recombinant USP1-UAF1-RAD51AP1 and reveal critical mechanistic details of the process.
- Fengshan Liang
- , Adam S. Miller
- & Patrick Sung
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Article
| Open AccessJNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression
LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.
- Jian Liu
- , Tianyuan Wang
- & Francesco J. DeMayo
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Article
| Open AccessThe deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors
Deubiquitinases have been shown to be involved in double strand break repair pathways. Here the authors reveal that USP15 deybiquitinase plays a role in homologues recombination repair by targeting BARD1 and affecting cells response to PARP inhibitors.
- Yihan Peng
- , Qingchao Liao
- & Huadong Pei
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Article
| Open AccessUfbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR
IRE1 and PERK, both important mediators of the unfold protein response pathway, are differentially regulated during plasma cell differentiation. Here the authors show that an ufmylation target, Ufbp1, suppresses PERK to stimulate plasma cell development and is induced by the IRE1/XBP1 pathway to promote ER expansion .
- Huabin Zhu
- , Brinda Bhatt
- & Nagendra Singh
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Article
| Open AccessIRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling
ER stress and UPR are implicated in various cancers. Here, the authors show that one of the canonical UPR pathways, IRE1α-XBP1 regulates c-MYC signaling to promote prostate tumorigenesis, and pharmacological inhibition of IRE1α with MKC8866 inhibits prostate cancer growth and synergizes with clinically used prostate cancer drugs.
- Xia Sheng
- , Hatice Zeynep Nenseth
- & Fahri Saatcioglu
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Article
| Open AccessTip60- and sirtuin 2-regulated MARCKS acetylation and phosphorylation are required for diabetic embryopathy
Neural tube defects can arise from high glucose levels caused by maternal diabetes, and MARCKS is required for neural tube closure. Here, Yang et al. show that acetylation and phosphorylation of MARCKS in hyperglycemic conditions causes mitochondrial and ER stress, leading to neural tube defects.
- Penghua Yang
- , Cheng Xu
- & Peixin Yang
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Article
| Open AccessPharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis
Imbalanced proteostasis is associated with diverse diseases, including ischemia/reperfusion injury in the heart. Here the authors show that the ATF6 arm of the unfolded protein response can be pharmacologically activated with a small molecule in vivo, providing protection from ischemia/reperfusion injury in the heart, the brain, and the kidney.
- Erik A. Blackwood
- , Khalid Azizi
- & Christopher C. Glembotski
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Article
| Open AccessStabilization of cytokine mRNAs in iNKT cells requires the serine-threonine kinase IRE1alpha
Invariant natural killer T (iNKT) cells rapidly enhance cytokine secretion and effector function following activation, but the underlying mechanism is still unclear. Here the authors show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α, activates the p38 kinase to stabilize cytokine mRNA for enhanced iNKT functions.
- Srinath Govindarajan
- , Djoere Gaublomme
- & Michael B. Drennan
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Article
| Open AccessNeurohormonal signaling via a sulfotransferase antagonizes insulin-like signaling to regulate a Caenorhabditis elegans stress response
Reduced insulin-like signaling is required for C. elegans response to many environmental stressors, but how distinct outcomes are achieved is unknown. The authors show that the cytosolic sulfotransferase SSU-1 controls neurohormonal signaling via NHR-1 to specify the animals’ osmotic stress response.
- Nicholas O. Burton
- , Vivek K. Dwivedi
- & H. Robert Horvitz
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Article
| Open AccessEpithelial cells release adenosine to promote local TNF production in response to polarity disruption
Epithelial stress can disrupt polarity and activate TNF and JNK signalling that contributes to inflammation and cell damage. Here, the authors show that disruption of apico-basal polarity leads to adenosine release, activating TNF and JNK and driving an inflammatory response during chronic stress.
- Ingrid Poernbacher
- & Jean-Paul Vincent
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Article
| Open AccessNEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress
Protein NEDDylation increases upon proteotoxic stress but the function of this response remains to be elucidated. Here, the authors show that NEDDylation contributes to the cellular defence against proteotoxicity by promoting nuclear protein aggregation and protecting the ubiquitin proteasome system.
- Chantal M. Maghames
- , Sofia Lobato-Gil
- & Dimitris P. Xirodimas
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Article
| Open AccessChemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction
Excessive production of reactive oxygen species (ROS) is associated with cardiac dysfunction, but the causal role of ROS remains poorly understood. Here the authors use an in vivo chemogenetic approach to develop a heart failure model in which generation of hydrogen peroxide in the heart leads to systolic heart failure without fibrotic remodeling.
- Benjamin Steinhorn
- , Andrea Sorrentino
- & Thomas Michel
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Article
| Open AccessSystemic signaling contributes to the unfolded protein response of the plant endoplasmic reticulum
The unfolded protein response (UPR) maintains cellular function under ER stress. While typically considered cell autonomous, here Lai et al. show that in Arabidopsis the UPR also has a systemic component triggered by intercellular movement of at least one bZIP transcription factor.
- Ya-Shiuan Lai
- , Giovanni Stefano
- & Federica Brandizzi
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Article
| Open AccessA small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to loss of voluntary muscle movement. Here, the authors screen for molecules that disrupt interaction between SOD1, a protein linked to ALS, and Derlin-1, and find an inhibitor that reduces pathology in an ALS mouse model.
- Naomi Tsuburaya
- , Kengo Homma
- & Hidenori Ichijo
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Article
| Open AccessCellular stress alters 3′UTR landscape through alternative polyadenylation and isoform-specific degradation
The function and consequences of alternative polyadenylation (APA) in stressed cells are largely unclear. Here, the authors show that stress-induced mRNA degradation depends on 3′UTR length and that APA-mediated 3′UTR shortening is an adaptive stress response mechanism for selective transcript stabilization.
- Dinghai Zheng
- , Ruijia Wang
- & Bin Tian
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Article
| Open AccessAlternative assembly of respiratory complex II connects energy stress to metabolic checkpoints
Mitochondrial complex II is normally composed of four subunits. Here the authors show that bioenergetic stress conditions give rise to a partially assembled variant of complex II, which shifts the anabolic pathways to less energy demanding processes.
- Ayenachew Bezawork-Geleta
- , He Wen
- & Jiri Neuzil
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Article
| Open AccessNon-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy
DAPK2 is a calmodulin-regulated protein kinase implicated in autophagy regulation, but how physiological stress leads to its activation is yet unknown. Here, the authors show that the central metabolic sensor AMPK phosphorylates DAPK2 to promote autophagy in a calmodulin-independent mechanism.
- Ruth Shiloh
- , Yuval Gilad
- & Adi Kimchi
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Article
| Open AccessPHA-4/FoxA senses nucleolar stress to regulate lipid accumulation in Caenorhabditis elegans
Nucleolar stress can disrupt ribosome biogenesis and in turn energy metabolism and lipid storage, but how this is regulated is unclear. Here, the authors show in C. elegans that the transcription factor PHA-4/FOXA acts as a sensor for nucleolar stress and can regulate expression of lipogenic genes
- Jieyu Wu
- , Xue Jiang
- & Bin Liang
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Article
| Open AccessHypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury
Myocardial ischemia–reperfusion injury stabilizes the hypoxia-inducible factor HIF2-alpha. Here, the authors show that HIF2-alpha protects the heart from injury via induction of the epidermal growth factor amphiregulin, and that amphiregulin administration is cardioprotective in mice.
- Michael Koeppen
- , Jae W. Lee
- & Holger K. Eltzschig
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Article
| Open AccessMultiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts
During S phase of the cell cycle, transcription and replication need to be coordinated in order to avoid conflicts leading to potential genomic instability. Here, the authors find that Mrc1 integrates signals from different kinases to regulate replication during unscheduled transcription events.
- Alba Duch
- , Berta Canal
- & Francesc Posas