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Article
| Open AccessTFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs. Here, the authors show that TFEB is the primary driver of renal disease and mTORC1 hyperactivation in TSC.
- Nicola Alesi
- , Damir Khabibullin
- & Elizabeth P. Henske
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Article
| Open AccessVariants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
A vesicle trafficking Rab11 effector switch is important for ciliogenesis. Here, the authors report a ciliopathy-related disorder caused by variants in WDR44, a Rab11 effector. WDR44 variants show higher affinity for Rab11 and can impair ciliogenesis.
- Andrea Accogli
- , Saurabh Shakya
- & Christopher J. Westlake
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Article
| Open AccessDeletion of Aurora kinase A prevents the development of polycystic kidney disease in mice
Using different mouse models of Polycystic Kidney Disease, this research demonstrated that deletion of the Aurora Kinase A gene was able to prevent cyst initiation and growth, identifying it as a central regulator of pathogenesis in this condition.
- Ming Shen Tham
- , Denny L. Cottle
- & Ian M. Smyth
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Article
| Open AccessMulti-scale structures of the mammalian radial spoke and divergence of axonemal complexes in ependymal cilia
Radial spokes (RS) are crucial in coordinating ciliary motility. Here, authors use cryo-EM and cryo-ET to gain insight into mammalian RS divergence in ependymal cilia, RS assembly mechanism and the structure-function relationships of ciliary and flagellar axonemes.
- Xueming Meng
- , Cong Xu
- & Yao Cong
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Article
| Open AccessA role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
- Haopeng Lin
- , Kunimasa Suzuki
- & Patrick E. MacDonald
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Article
| Open AccessNuclear Hsp104 safeguards the dormant translation machinery during quiescence
During aging, proteins are damaged and can misfold, compromising cellular viability. Here, Kohler et al. uncover how aging cells maintain fitness by redirecting the protein repair factor Hsp104 to the nucleus in response to metabolic cues.
- Verena Kohler
- , Andreas Kohler
- & Sabrina Büttner
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Article
| Open AccessLongevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans
Mechanotransduction can be defined as translating physical forces into gene expression, which subsequently drives cell fate. Here, Teuscher et al. showed that mechanotransduction across multiple tissues and extracellular matrices is essential for promoting longevity in vivo.
- Alina C. Teuscher
- , Cyril Statzer
- & Collin Y. Ewald
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Article
| Open AccessOligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension
The cell biological mechanisms that govern myelin sheath extension remain incompletely understood. Here, the authors find that calcium signaling in oligodendrocytes is required for the actin-dependent extension of myelin sheaths.
- Manasi Iyer
- , Husniye Kantarci
- & J. Bradley Zuchero
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Article
| Open AccessTRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence
Here, the authors show that TRIM28-mediated SUMOylation of SARS-CoV-2 NP is critical for its liquid-liquid phase separation (LLPS) property and subsequent inhibition of innate antiviral immunity. The peptide NSIP-III is applied to unleash such connection by interfering TRIM28 and NP interaction.
- Jiang Ren
- , Shuai Wang
- & Long Zhang
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Article
| Open AccessTargeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) represents a high-risk B-ALL subtype. Here the authors report that Th17 cells and IL-17A expression are elevated in Ph+ B-ALL patients and that targeting IL-17A enhances imatinib efficacy in preclinical models.
- Feng Wang
- , Yunxuan Li
- & Bing Cui
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Article
| Open AccessAngiogenesis-on-a-chip coupled with single-cell RNA sequencing reveals spatially differential activations of autophagy along angiogenic sprouts
The functional heterogeneity of autophagy in endothelial cells during angiogenesis remains incompletely understood. Here, the authors apply a 3D angiogenesis-on-a-chip coupled with single-cell RNA sequencing to find distinct autophagy functions in two different endothelial cell populations during angiogenic sprouting.
- Somin Lee
- , Hyunkyung Kim
- & Noo Li Jeon
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Perspective
| Open AccessMembrane transformations of fusion and budding
Life-crucial membrane fusion and budding were traditionally viewed with electron microscopy. With recent breakthroughs that visualize membrane transformation in real time, Wu and Chan synthesize a new model with mechanistic principles and functions.
- Ling-Gang Wu
- & Chung Yu Chan
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Article
| Open AccessCell cycle arrest induces lipid droplet formation and confers ferroptosis resistance
How cell cycling coordinates with cell survival and death remains unclear. Here, the authors reveal a suppressive effect of cell cycle arrest on ferroptosis and propose a ferroptosis-inducing approach to treat slow-cycling, therapy-resistant cancers.
- Hyemin Lee
- , Amber Horbath
- & Boyi Gan
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Article
| Open AccessTMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress
Lysosomes are critical regulators of cellular homeostasis. Here, the authors report that the lysosomal protein TMEM55B orchestrates cellular response to acute oxidative stress by coordinating autophagosome degradation, lysosomal repair, and activation of transcriptional stress responses.
- Eutteum Jeong
- , Rose Willett
- & Rosa Puertollano
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Article
| Open AccessMcam inhibits macrophage-mediated development of mammary gland through non-canonical Wnt signaling
Mammary epithelial cells act to continuously renew the mammary tissue and must balance differentiation and self-renewal. Here they show that Mcam, a non-canonical Wnt pathway member, regulates communication between macrophages and mammary epithelial cells, thereby maintaining self-renewal and subsequently promoting mammary ductal morphogenesis.
- Xing Yang
- , Haibo Xu
- & Baowei Jiao
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Article
| Open AccessSpatial structure, chemotaxis and quorum sensing shape bacterial biomass accumulation in complex porous media
Pores and channels within complex porous structures, such as the soil or the human gut, influence fluid flow and thus bacterial colonization. Here, Scheidweiler et al. study bacterial colonization of a model complex porous structure and show how the interactions between fluid flow, microscale structure, chemotaxis, and gradients of a quorum-sensing signaling molecule control the heterogenous accumulation of bacterial biomass.
- David Scheidweiler
- , Ankur Deep Bordoloi
- & Pietro de Anna
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Article
| Open AccessHijacking of internal calcium dynamics by intracellularly residing viral rhodopsins
Rhodopsins are ubiquitous light-driven membrane proteins that have diverse functions in nature, and value as optogenetics tools. Here the authors characterise type 1 viral channelrhodopsins, showing that they regulate intracellular calcium and can be used for the photocontrol of muscle contraction in vivo.
- Ana-Sofia Eria-Oliveira
- , Mathilde Folacci
- & Michel Vivaudou
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Article
| Open AccessExperimental determination and mathematical modeling of standard shapes of forming autophagosomes
Autophagosome formation involves membrane morphological changes. Here, authors statistically determined average shapes of forming autophagosomes from 3D electron micrographs and established a theoretical model that quantitatively reproduces them.
- Yuji Sakai
- , Satoru Takahashi
- & Noboru Mizushima
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Article
| Open AccessThe evolution of centriole degradation in mouse sperm
Centrioles have a conserved structure and function but have diversified in sperm. Here the authors provide insight into the molecular mechanisms and adaptive evolution underlying this diversification.
- Sushil Khanal
- , Ankit Jaiswal
- & Tomer Avidor-Reiss
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Article
| Open AccessCovalent PARylation of DNA base excision repair proteins regulates DNA demethylation
The PARylation activity of PARP recruits DNA repair proteins to damaged DNA, most likely via non-covalent protein-PAR interactions. Here, the authors show that PARP1 covalently PARylates base excision repair proteins to modulate their DNA transactions and thus promote active BER DNA demethylation.
- Simon D. Schwarz
- , Jianming Xu
- & Roland Steinacher
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Article
| Open AccessMulti-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
The molecular characteristics and therapeutic vulnerabilities of TFCP2-rearranged rhabdomyosarcomas (RMS) require further exploration. Here, the authors use multi-omics analyses and functional and mechanistic investigations to characterize TFCP2-rearranged RMS – including cases with FUS/EWSR1-TFCP2 fusions – across two precision oncology programs.
- Julia Schöpf
- , Sebastian Uhrig
- & Claudia Scholl
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Article
| Open AccessAI-driven projection tomography with multicore fibre-optic cell rotation
Conventional optical tomography can have disadvantages, including anisotropic resolution and incomplete imaging of cellular structures. Here, the authors propose an AI-driven 3D cell imaging system with a cell rotator, which offers improved resolution and automated processing.
- Jiawei Sun
- , Bin Yang
- & Juergen W. Czarske
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Article
| Open AccessSTYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation
The sperm flagellum is composed of tubulin-based microtubules and is critical for sperm motility and thus male fertility. Here, the authors show that STYXL1 regulates CCT complex-facilitated tubulin folding and is essential for sperm flagella formation.
- Yu Chen
- , Mengjiao Luo
- & Xuejiang Guo
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Article
| Open AccessHuman apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation
Airway organoids made in Matrigel are in basal-out orientation. Here, authors present apical-out nasal organoids using a biochemically defined hydrogel system, revealing that matrix metalloproteinases are required for normal epithelial development.
- Liyue Li
- , Linyi Jiao
- & Chunwei Li
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Article
| Open AccessMammalian cell growth characterisation by a non-invasive plate reader assay
Automated and non-invasive mammalian cell analysis is currently lagging behind due to a lack of methods suitable for a variety of cell lines and applications. Here the authors develop a high throughput non-invasive method for tracking suspension and adhesion mammalian cell growth based on plate reader measures to characterize engineered cell lines.
- Alice Grob
- , Chiara Enrico Bena
- & Francesca Ceroni
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Article
| Open AccessSerglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration
Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.
- Fan Chen
- , Linchuan Lei
- & Jianru Wang
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Article
| Open AccessStabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
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Article
| Open AccessInnate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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Article
| Open AccessMic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
The molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, authors uncover a role for the EMC2- SLC25A46-Mic19 axis in mitochondrial lipid metabolism and liver disease
- Jun Dong
- , Li Chen
- & He He
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Article
| Open AccessMCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation
B cell activation and differentiation entails metabolic remodelling, involving differential utilisation of monocarboxylates such as L-lactate and pyruvate. Here authors show by B-cell-specific genomic deletion of monocarboxylate transporter 1 (MCT1) that the consequential scarcity of pyruvate results in decreased acetylation of Histone H3 at K27, leading to decreased AID transcription and deficient class switching to IgG.
- Wenna Chi
- , Na Kang
- & Ligong Chen
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessBACH1 controls hepatic insulin signaling and glucose homeostasis in mice
Hepatic insulin resistance plays a central role in metabolic syndrome. Here, the authors show that transcription factor BACH1 acts as a negative regulator of insulin signaling and that hepatic BACH1 deficiency ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or diabetic mice
- Jiayu Jin
- , Yunquan He
- & Dan Meng
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Article
| Open AccessRedox-enabled electronic interrogation and feedback control of hierarchical and networked biological systems
With redox-linked synthetic biology and electrobiofabrication, electronic information can be transmitted in a bidirectional manner between biology and electronics. Here the authors design an electrogenetic platform that allows real time electronic control of biological functions from proteins and gene circuits to cell consortia.
- Sally Wang
- , Chen-Yu Chen
- & William E. Bentley
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Article
| Open AccessUnique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice
Invariant natural killer T (iNKT) cells have recently been reported to play a key role in adipose tissue homeostasis. Here, the authors show that adipose tissue iNKT cells mediate immune responses that control adipocyte turnover in mice.
- Sang Mun Han
- , Eun Seo Park
- & Jae Bum Kim
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Article
| Open AccessVWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes
mTORC1 adapts cellular metabolism in response to nutrient signals. Here, the authors identify VWCE as a negative regulator of amino acid-dependent mTORC1 signaling and a potential as a therapeutic target in prostate cancer treatments.
- Tianyu Zhao
- , Yuanyuan Guan
- & Ying Liu
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Article
| Open AccessForce transmission by retrograde actin flow-induced dynamic molecular stretching of Talin
Focal adhesion proteins transmit intracellular forces to the extracellular matrix (ECM). Here, the authors show a force transmission by elastic transient clutch of Talin between ECM and constantly flowing F-actin at focal adhesions.
- Sawako Yamashiro
- , David M. Rutkowski
- & Naoki Watanabe
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Article
| Open AccessMtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
Excessive lipid accumulation in hepatocytes causes fatty liver disease and liver failure. Here the authors show that ablation of Mitochondrial Fission Process 1 in hepatocytes in mice protects fatty liver disease and dysfunction caused by high fat diet.
- Cecilia Patitucci
- , Juan Diego Hernández-Camacho
- & Timothy Wai
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Article
| Open AccessAdult stem cell activity in naked mole rats for long-term tissue maintenance
Authors report that long-term intestinal tissue maintenance in naked mole rats is achieved by having an expanded pool of slow-dividing adult stem cells while a higher proportion of differentiated cells confer enhanced function and protection to the intestinal mucosa.
- Shamir Montazid
- , Sheila Bandyopadhyay
- & Shazia Irshad
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Article
| Open AccessMechanical control of neural plate folding by apical domain alteration
Theoretical and experimental observations argue that apical domain heterogeneity in the neural plate is a tug-of-war contest between constricted and elongated cells. This competition likely reflects mechanical forces operating during tissue bending.
- Miho Matsuda
- , Jan Rozman
- & Sergei Y. Sokol
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Article
| Open AccessNEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62
Selective autophagy helps to degrade aggregated proteins accumulating in neurodegenerative diseases. Here, the authors show that NEMO, a ubiquitin binding protein previously linked to innate immune signaling, is recruited to misfolded proteins and promotes their autophagic clearance by forming condensates with the autophagy receptor p62.
- Nikolas Furthmann
- , Verian Bader
- & Konstanze F. Winklhofer
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Article
| Open AccessA DARPin promotes faster onset of botulinum neurotoxin A1 action
Botulinum neurotoxins (BoNTs), the causative agents of the disease botulism, are potent biological toxins. Here the authors use Designed Ankyrin Repeat Proteins (DARPins) to probe BoNT structure and function: DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro was identified.
- Oneda Leka
- , Yufan Wu
- & Richard A. Kammerer
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Article
| Open AccessFunctional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing
Spatially resolved metabolism in complex tissues is vital but poorly understood. Here, the authors establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism at single-cell resolution to organ-wide physiology.
- Jack Holcombe
- & Helen Weavers
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Article
| Open AccessAutophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury
Understanding the role of GPX4 in cell ferroptosis at the interface of the inner cortex and medulla is crucial in the context of renal injury. Here, the authors demonstrate that the OTUD5 interaction with GPX4 is key in resisting ischemia/reperfusion-induced ferroptosis in renal cells, offering a new strategy for treating acute kidney injury.
- Li-Kai Chu
- , Xu Cao
- & Jun Liu
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Article
| Open AccessCdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
The role of Cdo1 in exercise-mediated metabolic health and NAFLD is not clear. Here, the authors show that hepatic Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling to blunt hepatosteatosis and to promote exercise-mediated alleviation of NAFLD in mice.
- Min Chen
- , Jie-Ying Zhu
- & Liang Guo
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Article
| Open AccessDissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans
To overcome challenges posted by vast number of GPCR genes and redundancy, the authors disrupted nearly all GPCR-encoding genes in C. elegans, enabling effective examination of GPCR signaling and offering a valuable resource for the research community.
- Longjun Pu
- , Jing Wang
- & Changchun Chen
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Review Article
| Open AccessMolecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology
- Nieves Montenegro-Navarro
- , Claudia García-Báez
- & Melissa García-Caballero
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Article
| Open AccessChemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
Deregulation of BCL-2 proteins ensures resistance to apoptosis. Here, the authors describe cytosolic BAX dimers, which in cancer cells inhibit BAX activation and they develop a strategy to modulate BAX dimers to potentiate BAX-mediated apoptosis.
- Nadege Gitego
- , Bogos Agianian
- & Evripidis Gavathiotis
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Article
| Open AccessRho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles
Cell movements are achieved by the spatio-temporal coordination of local membrane protrusions and retractions. Here, the authors identify a mechanism by which these protrusion and retraction events are coupled and how this affects the directionality of cell movements.
- Suchet Nanda
- , Abram Calderon
- & Leif Dehmelt
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Article
| Open AccessThe function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways
Berkane et al. investigated the activation process of selective autophagy of the ER. They show that that phosphorylation of FAM134 proteins by CK2 is a prerequisite for the formation of large micro-clusters of high-density at the ER membrane.
- Rayene Berkane
- , Hung Ho-Xuan
- & Alexandra Stolz
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