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| Open AccessRescue of mitochondrial import failure by intercellular organellar transfer
Mitochondrial biogenesis and maintenance relies on protein import from the cytosol. Here, authors show that import failure impacts organelle structure and dynamics. They also identify a rescue mechanism involving intercellular mitochondrial transfer.
- Hope I. Needs
- , Emily Glover
- & Ian Collinson
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Article
| Open AccessR-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient
Left-right (LR) body asymmetry is established by leftward flow in the LR organizer. Here, the authors show in Xenopus that R-Spondin 2 acts as an FGF receptor antagonist that produces a right-to-left FGF signaling gradient in response to flow to break LR symmetry.
- Hyeyoon Lee
- , Celine Marie Camuto
- & Christof Niehrs
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Article
| Open AccessMitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity
Stress-independent autophagy is less understood than stress-induced autophagy and is important for thymic self-tolerance. Here the authors show that a mitochondrial protein C15ORF48 is important for stress-independent autophagy and alters glutathione metabolism and C15orf48 knockout mice develop autoimmunity and changes to thymic epithelial cells.
- Yuki Takakura
- , Moeka Machida
- & Noritaka Yamaguchi
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Article
| Open AccessTissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans
Wang et al. profile age-dependent miRNAomic changes in worm tissues and extracellular vesicles (EVs). They show that ageing controls miRNAs in a tissue-specific manner and their findings further suggest a complex EV-mediated miRNA trafficking network across tissues.
- Xueqing Wang
- , Quanlong Jiang
- & Yidong Shen
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Article
| Open AccessRan-GTP assembles a specialized spindle structure for accurate chromosome segregation in medaka early embryos
Mitotic spindle assembles in each blastomere to segregate duplicated chromosomes during cleavage of the fertilized egg. Here, the authors establish functional assays in fish embryos and find that Ran-GTP assembles a microtubule network at the metaphase spindle center that is essential for chromosome segregation.
- Ai Kiyomitsu
- , Toshiya Nishimura
- & Tomomi Kiyomitsu
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Article
| Open AccessHRDE-2 drives small RNA specificity for the nuclear Argonaute protein HRDE-1
Argonaute proteins are loaded with small RNAs to confer target RNA specificity and proper gene silencing. Here, the authors establish that HRDE-2 recruits the unloaded nuclear Argonaute HRDE-1 to germ granules to facilitate correct small RNA loading.
- Shihui Chen
- & Carolyn M. Phillips
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Article
| Open AccessDENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy
Small GTPases such as Rabs control the positioning of lysosomes. Here, the authors unveil a molecular cascade orchestrated by Arl8/DENND6A/Rab34 that regulates lysosome location, impacting autophagy.
- Rahul Kumar
- , Maleeha Khan
- & Peter S. McPherson
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Article
| Open AccessMolecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy
The balance between apoptosis and autophagy is critical for normal development, proper tissue function, and disease pathogenesis. Here, the authors show previously unannotated BIRC6 domains, including a ubiquitin-like domain, and how it utilizes its ubiquitylation function to regulate both apoptosis and autophagy.
- Shuo-Shuo Liu
- , Tian-Xia Jiang
- & Xiao-Bo Qiu
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Article
| Open AccessExpression of E-cadherin by CD8+ T cells promotes their invasion into biliary epithelial cells
The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been associated with primary biliary cholangitis. Here, the authors demonstrate that CD8+ T cells invade BEC using a mechanism that is dependent on cytoskeletal rearrangements and E-cadherin:β-catenin interactions.
- Scott P. Davies
- , Vincenzo Ronca
- & Ye H. Oo
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Article
| Open AccessNuclear and cytoplasmic specific RNA binding proteome enrichment and its changes upon ferroptosis induction
The reported assay shows a subcellular-specific RNA labeling method for efficient enrichment and deep profiling of nuclear and cytoplasmic RBPs, the authors apply this to investigate changes of subcellular-specific RBP-RNA interactions in ferroptosis.
- Haofan Sun
- , Bin Fu
- & Weijie Qin
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Article
| Open AccessA universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle
Succinate dehydrogenase converts malate to enoloxaloacetate, a metabolically inactive and inhibitory side product of the TCA cycle. Here, Zmuda et al. describe a conserved metabolite damage repair enzyme that can remove enol-oxaloacetate and is critical for efficient aerobic respiration.
- Anthony J. Zmuda
- , Xiaojun Kang
- & Thomas D. Niehaus
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Article
| Open AccessFLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress
Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.
- Jessica D. Tischler
- , Hiroshi Tsuchida
- & Richard O. Adeyemi
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Article
| Open AccessRNA polymerase II pausing is essential during spermatogenesis for appropriate gene expression and completion of meiosis
Gene expression dynamics are tightly regulated during spermatogenesis, with disruptions resulting in infertility. Here they identify a critical role for RNA PolII pausing in spermatogenesis and show that loss of the RNA PolII pausing factor NELF causes meiotic arrest.
- Emily G. Kaye
- , Kavyashree Basavaraju
- & Prabhakara P. Reddi
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Article
| Open AccessCaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses
Calmodulin-dependent kinase 4 (CaMK4) has been implicated in humoral immunity. Here, the authors demonstrate that CaMK4 expression controls the differentiation of T follicular helper cells, leading to the expansion of pathogenic B cells in systemic lupus erythematosus.
- Marc Scherlinger
- , Hao Li
- & George C. Tsokos
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Article
| Open AccessMitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging
Dysregulated autophagy and mitochondrial function are two well-described hallmarks of aging. Here, the authors describe an unexpected age-associated upregulation of mitophagy in response to neuroinflammation triggered by leaked mtDNA.
- Juan Ignacio Jiménez-Loygorri
- , Beatriz Villarejo-Zori
- & Patricia Boya
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Article
| Open AccessActivation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis
Whether Kupffer cells play a role in regulating the pathogenesis of fatty liver disease remains to be completely explored. Here, the authors show GPR3 activation stimulates glycolysis in Kupffer cells through GPR3-β-arrestin2-GAPDHPKM2 pathway and inhibits high-fat diet induced obesity and liver pathogenesis.
- Ting Dong
- , Guangan Hu
- & Jianzhu Chen
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Article
| Open AccessMARC-3, a membrane-associated ubiquitin ligase, is required for fast polyspermy block in Caenorhabditis elegans
In many sexually reproducing animals, the oocyte fuses with only one sperm during fertilization. Here, the authors show that C. elegans MARC-3, a membrane-associated RING-CH-type ubiquitin ligase, regulates polyspermy block after fertilization and maternal membrane protein degradation during the oocyte-to-embryo transition.
- Ichiro Kawasaki
- , Kenta Sugiura
- & Ken Sato
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Article
| Open AccessIntraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function
Longitudinal monitoring of liver function in vivo is hindered by the lack of high-resolution non-invasive imaging techniques. Here, the authors show a crucial and unique tool for longitudinal in vivo imaging of liver spheroids at cellular resolution to study liver physiology and disease.
- Francesca Lazzeri-Barcelo
- , Nuria Oliva-Vilarnau
- & Per-Olof Berggren
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Article
| Open AccessEmergence of periodic circumferential actin cables from the anisotropic fusion of actin nanoclusters during tubulogenesis
Periodic circumferential cytoskeletons support biological tube formation. Here, the authors show that self-assembled actin nanoclusters undergo biased fusion and develop into periodic cables in response to the membrane anisotropy of the expanding Drosophila tracheal tube.
- Sayaka Sekine
- , Mitsusuke Tarama
- & Shigeo Hayashi
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Article
| Open AccessMethionine aminopeptidase 2 and its autoproteolysis product have different binding sites on the ribosome
The role of methionine aminopeptidase 2 (MAP2) at the ribosome goes beyond N-terminal methionine excision. Klein et al. use cryo-EM to identify a second MAP2 binding site on the ribosome, and describe the dynamic interactions of MAP2 at the ribosome.
- Marius A. Klein
- , Klemens Wild
- & Irmgard Sinning
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Article
| Open AccessProteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis
The nature of SEL1L-HRD1 ERAD substrates remains unclear. Here, the authors identified ~100 endogenous substrates, and showed that SEL1L-HRD1 ERAD is indispensable for the activity of GPI transamidase complex and the biogenesis of GPI-anchored proteins.
- Xiaoqiong Wei
- , You Lu
- & Ling Qi
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Article
| Open AccessATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover
Lipophagy is the degradation of lipid droplets by the autophagy machinery. Here, the authors identify that autophagy protein ATG14 also targets lipid droplets and interacts with ATG8 proteins, functioning as an autophagic receptor for STX18-regulated lipophagy.
- Zhen Yuan
- , Kun Cai
- & Binbin Ding
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Article
| Open AccessCell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
It has been reported that the circadian clock regulator Bmal1 can modulate tumorigenesis. Here the authors show that ectopic expression of Bmal1 promotes an immune resistant mesenchymal melanoma cell state associated with increased AP-1 activity.
- Xue Zhang
- , Shishir M. Pant
- & Chi V. Dang
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Article
| Open AccessProteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly
Here, the authors uncover that, among 92 identified host factors associated with SARS-CoV-2 virions, G3BP1 and G3BP2 are present at the assembly site, incorporated within virions, and unexpectedly promote the production of SARS-CoV-2 virions.
- Emilie Murigneux
- , Laurent Softic
- & Sarah Gallois-Montbrun
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Article
| Open AccessTwo mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality
Chiang et al. map a genetic interaction in animal mitochondrial DNA by recombination. This reveals how polymorphisms in two complex IV subunits jointly affect cardiolipin binding to impact complex stability, organismal fitness and disease expression.
- Ason C. Y. Chiang
- , Jan Ježek
- & Hansong Ma
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Article
| Open AccessSoluble and multivalent Jag1 DNA origami nanopatterns activate Notch without pulling force
The Notch receptor is known to be activated by a pulling force, but whether it is strictly required remains to be clarified. Here, the authors demonstrate activation of Notch through soluble multivalent DNA origami constructs, showing effects in neuroepithelial-like stem cells.
- Ioanna Smyrlaki
- , Ferenc Fördős
- & Björn Högberg
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Article
| Open AccessConserved chromatin and repetitive patterns reveal slow genome evolution in frogs
Frogs are an ancient and ecologically diverse group of amphibians that include important model systems. This paper reports genome sequences of multiple frog species, revealing remarkable stability of frog chromosomes and centromeres, along with highly recombinogenic extended subtelomeres.
- Jessen V. Bredeson
- , Austin B. Mudd
- & Daniel S. Rokhsar
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Article
| Open AccessNAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
How age-accumulated mtDNA mutations in the small intestine modulate intestinal homeostasis is unclear. Here, the authors show that increased mtDNA mutation burden triggers an ATF5 dependent UPRmt by NAD+ depletion, and thus regulates intestinal aging through impaired Wnt/β-catenin signaling.
- Liang Yang
- , Zifeng Ruan
- & Xingguo Liu
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Article
| Open AccessThe phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
The T cell receptor signalosome integrates multiple positive and negative regulatory elements to finetune the response and limit harmful inflammation. Here authors show a regulatory cascade of T cell activation, in which DUSP22 negatively regulates UBR2, which is an activator of the kinase Lck via K63 ubiquitination.
- Ying-Chun Shih
- , Hsueh-Fen Chen
- & Tse-Hua Tan
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Article
| Open AccessApoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis
Mucins on the surface of healthy T cells limit their phagocytic uptake by macrophages. Here the authors show that upon apoptosis induction in T cells, surface mucins are cleaved and released by ADAM10 to promote efferocytosis of the apoptotic cells.
- Linnea Z. Drexhage
- , Shengpan Zhang
- & Quentin J. Sattentau
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Article
| Open AccessAmyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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Article
| Open AccessStructural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes
UAP56 is an important factor in the TREX complex, which is responsible for mRNA export. Here the authors show that the closely related RNA helicases, UAP56 and URH49, exhibit different three-dimensional structures due to one amino acid change. Accordingly, they form distinct apo-complexes and function in the nuclear export of specific target mRNAs.
- Ken-ichi Fujita
- , Misa Ito
- & Seiji Masuda
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Article
| Open AccessSingle-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol
Stimulator of interferon genes (STING) is known to translocate from ER to Golgi while orchestrating type I interferon responses to DNA. Here, the authors show single-molecule resolution images of STING clustering at the trans-Golgi network, where it acts as a scaffold to trigger downstream signaling.
- Haruka Kemmoku
- , Kanoko Takahashi
- & Tomohiko Taguchi
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Article
| Open AccessOXR1 maintains the retromer to delay brain aging under dietary restriction
Dietary restriction promotes healthy brain aging, but the mechanism is unknown. Here, the authors show that OXR1 is upregulated by dietary restriction and confers age-related neuroprotection by maintaining retromer-mediated protein and lipid trafficking.
- Kenneth A. Wilson
- , Sudipta Bar
- & Pankaj Kapahi
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Article
| Open AccessDiabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.
- Daewon Lee
- , Eunju Yoon
- & Jongkyeong Chung
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Article
| Open AccessEpstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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Article
| Open AccessUpregulated pexophagy limits the capacity of selective autophagy
An accumulation of one substrate of selective autophagy can lead to autophagic degradation deficiencies. Here, the authors show that a pathogenic increase in a single autophagy pathway restricts another by consuming the cell’s autophagy capacity.
- Kyla Germain
- , Raphaella W. L. So
- & Peter K. Kim
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Article
| Open AccessN-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line
IgG molecules are glycosylated at a conserved asparagine residue of their constant region, and this modification is essential for the effector functions of their soluble form, such as complement activation and binding to Fcɣ receptors. Here authors show that in a model B-cell line, neither the expression nor the function of the membrane-bound form of IgG depend on glycosylation.
- Theresa Kissel
- , Veerle F. A. M. Derksen
- & René E. M. Toes
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Article
| Open AccessLFA-1 nanoclusters integrate TCR stimulation strength to tune T-cell cytotoxic activity
CD8+ T cell activation involves cooperation between the T cell receptor and the integrin LFA-1. Here authors show how LFA-1 nanoclusters participate in the calibration of TCR stimulation strength and activation of cytotoxic function in CD8+ T cells.
- Claire Lacouture
- , Beatriz Chaves
- & Loïc Dupré
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Article
| Open AccessSustained rhoptry docking and discharge requires Toxoplasma gondii intraconoidal microtubule-associated proteins
The authors identified a series of cytoskeletal proteins involved in the discharge of invasion-related organelles in Toxoplasma gondii. They successfully delineated their functions through the utilization of expansion and cryo-electron microscopy.
- Nicolas Dos Santos Pacheco
- , Albert Tell i Puig
- & Dominique Soldati-Favre
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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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