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| Open AccessCdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila
Mitochondrial fission, performed by Drp1, is carefully regulated, particularly in neurons. Here, the authors examine Drosophila Cdk8/CDK19 function in mitochondrial fission and uncover a role phosphorylating Drp1 in the cytoplasm and show overexpression suppresses a Parkinson’s disease model.
- Jenny Zhe Liao
- , Hyung-lok Chung
- & Esther M. Verheyen
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Article
| Open AccessModulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif
Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. Here the authors obtain crystal structures and NMR data to show the recognition of diaromatic peptide motifs on a noncanonical surface of the PEX13 SH3 domain, revealing a dynamic network which modulates peroxisomal matrix import.
- Stefan Gaussmann
- , Rebecca Peschel
- & Michael Sattler
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Article
| Open AccessCross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies
The spatial mapping of proteins can give important functional insights. Here, Zhu et al. develop a cross-linking mass spectrometry-based spatial proteomics method that does not require protein engineering, affords sub-organelle resolution, and elucidates both protein locations and membrane topologies.
- Ying Zhu
- , Kerem Can Akkaya
- & Fan Liu
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Article
| Open AccessOptogenetic control of mRNA condensation reveals an intimate link between condensate material properties and functions
Biomolecular condensates play important roles in diverse cellular activities. Here the authors employ optogenetic tool and single-molecule mRNA imaging, showing that sequestering target mRNAs into condensates lead to translation inhibition.
- Min Lee
- , Hyungseok C. Moon
- & Yongdae Shin
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Article
| Open AccessDifferentiation granules, a dynamic regulator of T. brucei development
The African trypanosome Trypanosoma brucei has been shown to form stress granules in vitro that might be repurposed to enable differentiation and facilitate parasite transmission. Here, Cayla et al. show that differentiation between slender and stumpy forms does involve membrane-less granules that are different from nutritional stress granules.
- Mathieu Cayla
- , Christos Spanos
- & Keith R. Matthews
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Article
| Open AccessCholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds
Cholesterol lowering medication positively affects anti-cancer immune response, but the underpinning mechanism is not fully known. Here authors show that the effect is mediated by specific cholesterol binding motifs in STING, a key mediator of inflammation, via regulating its trafficking to Golgi.
- Bao-cun Zhang
- , Marlene F. Laursen
- & Martin R. Jakobsen
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Article
| Open AccessSNX8 enables lysosome reformation and reverses lysosomal storage disorder
Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.
- Xinran Li
- , Cong Xiang
- & Xin-Hua Feng
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Article
| Open AccessDefective mitochondria remodelling in B cells leads to an aged immune response
B cell activation in the germinal centre (GC) is accompanied by metabolic adaptation, but the functions of mitochondria remodelling during this process is unclear. Here the authors find that B cell-specific deficiency of Tfam, a transcription factor modulating mitochondria remodelling, impacts GC responses and induces aged immune features in B cells.
- Marta Iborra-Pernichi
- , Jonathan Ruiz García
- & Nuria Martínez-Martín
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Article
| Open AccessOsteocyte mitochondria regulate angiogenesis of transcortical vessels
Osteocytes are the key cellular components of cortical bone. Here they show that osteocytes transfer mitochondria to the endothelial cells of transcortical vessels (TCVs), which promotes angiogenesis and increases function of the TCV network.
- Peng Liao
- , Long Chen
- & Junjie Gao
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Article
| Open AccessThe AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions
Mitochondria emerged as essential actors of neural circuits development. Here, the authors uncovered that the AMPK-related kinase NUAK1 controls axonal mitochondrial metabolism through the regulation of the mitochondrial microprotein BRAWNIN.
- Marine Lanfranchi
- , Sozerko Yandiev
- & Julien Courchet
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Matters Arising
| Open AccessReply to: Does the KDEL receptor cycle between the Golgi and the ER?
- Jurgen Denecke
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Article
| Open AccessActivity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo
The mechanisms regulating mitochondrial architecture in neurons remain unclear. The authors report that in dendrites, mitochondria structure is specified by the CAMKK2-AMPK pathway through compartment-specific and activity-dependent levels of fission.
- Daniel M. Virga
- , Stevie Hamilton
- & Tommy L. Lewis Jr
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Article
| Open AccessSARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle
SARS-CoV-2 uses the host endolysosomal system for replication and egress. Here the authors show that SARS-CoV-2 virulence factor ORF3a localizes to the late endocytic compartments of the host cell to disrupt Rab7 GTP to GDP cycling and block lysosome function in cargo degradation, while activated Rab7 promotes virus replication.
- Kshitiz Walia
- , Abhishek Sharma
- & Amit Tuli
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Article
| Open AccessNDUFS4 regulates cristae remodeling in diabetic kidney disease
Mitochondrial Ndufs4, a subunit of complex I, is a regulator of the electron transport chain. Here, the authors show that forced expression of Ndufs4 in podocytes improves the assembly of respiratory supercomplexes, maintains cristae integrity, and mitigates the progression of diabetic kidney disease
- Koki Mise
- , Jianyin Long
- & Farhad R. Danesh
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Article
| Open AccessOrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools
Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.
- Ara Lee
- , Gihyun Sung
- & Kimoon Kim
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessTBC1D23 mediates Golgi-specific LKB1 signaling
The LKB1 signaling is differentially regulated and has distinct functions at different subcellular compartments. Tu et al reports that TBC1D23 specifically regulates Golgi-LKB1 signaling and link this pathway to neurodevelopment disorders.
- Yingfeng Tu
- , Qin Yang
- & Da Jia
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Article
| Open AccessReducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans
Synthesis of ribosomal RNA (rRNA) by Pol I sustains cell growth but is highly energy demanding. Here the authors show that curbing of Pol I activity lowers systemic energy utilization and delays metabolic aging by reducing triglyceride lipolysis and mitochondrial oxygen consumption.
- Samim Sharifi
- , Prerana Chaudhari
- & Maria Ermolaeva
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Article
| Open AccessStalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis
Ribosome associated quality control (RQC) is a new area of biological investigation with emerging connection to a broad range of diseases. Here authors show that mitochondrial stress can upregulate a new RQC pathway important for tissue homeostasis.
- Ji Geng
- , Shuangxi Li
- & Bingwei Lu
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Article
| Open AccessA SPLICS reporter reveals \({{{{{\boldsymbol{\alpha }}}}}}\)-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation
Mitochondria-lysosome interactions are fundamental to cellular physiology. Here, the authors describe a genetically-encoded SPLICS reporter to study short- and long-juxtapositions between mitochondria and lysosomes.
- Flavia Giamogante
- , Lucia Barazzuol
- & Marisa Brini
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Article
| Open AccessALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy
Allophagy eliminates paternal mitochondria in C. elegans embryos. This study reveals that an autophagy adaptor, ALLO-1, recognizes cargos and initiates autophagosome formation by gathering with the ULK complex in an IKKE-1 kinase-dependent manner.
- Taeko Sasaki
- , Yasuharu Kushida
- & Miyuki Sato
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Article
| Open AccessA system for inducible mitochondria-specific protein degradation in vivo
Conditional degradation of proteins is instrumental to advance our knowledge of cell biology but has been lacking for organelles like mitochondria. Here, the authors develop a proteolysis system based on the mycoplasma Lon protease that functions selectively within mitochondria in yeast and human cells.
- Swastika Sanyal
- , Anna Kouznetsova
- & Camilla Björkegren
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Article
| Open AccessStructural basis for regulated assembly of the mitochondrial fission GTPase Drp1
Structural and functional studies highlight the molecular regulation of assembling the mitochondrial division machinery. The core unit is closed, and specific interactions open this unit to facilitate assembly at the right place and time in cells.
- Kristy Rochon
- , Brianna L. Bauer
- & Jason A. Mears
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Article
| Open AccessDynamic nucleolar phase separation influenced by non-canonical function of LIN28A instructs pluripotent stem cell fate decisions
The role of nucleolar phase separation in stem cell fate decision is not well understood. Here, the authors show that the nucleolus-localized LIN28A protein undergoes LLPS in mESCs and in vitro, and that pluripotency state conversion depends on this phase separation capacity.
- Tianyu Tan
- , Bo Gao
- & Jin Zhang
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Article
| 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 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 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 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 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 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 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 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 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 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 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 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 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 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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Article
| Open AccessA single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs
Dey et al. use structure-function methods to show that partial mimicry of the coatomer-binding motif in the SARS-CoV-2 spike is crucial for its release post coatomer-dependent delivery, thus ensuring optimal spike fusogenicity and VLP incorporation.
- Debajit Dey
- , Enya Qing
- & S. Saif Hasan
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Article
| Open AccessPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.
- Helene Jahn
- , Ladislav Bartoš
- & Anant K. Menon
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Article
| Open AccessiU-ExM: nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy
Current expansion microscopy approaches need further optimization to achieve the precision of nanoscopy techniques. Here, the authors develop an iterative ultrastructure expansion microscopy (iU-ExM) approach that achieves SMLM-level resolution.
- Vincent Louvel
- , Romuald Haase
- & Paul Guichard
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Article
| Open AccessTime-resolved proteomic profiling reveals compositional and functional transitions across the stress granule life cycle
Stress granules (SGs) are dynamic compartments with a poorly characterized transition in composition and function during prolonged stress. In this study, the authors investigated the dynamic changes in SG constituents during acute to prolonged heat shock using time-resolved proteomic profiling.
- Shuyao Hu
- , Yufeng Zhang
- & Yun Bai
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Article
| Open AccessDynamical control enables the formation of demixed biomolecular condensates
In this work, the authors report that protein-RNA condensates with shared proteins and distinct RNAs can form and persist in vitro and in cells as distinct entities if the nonshared RNA molecules are dynamically arrested, but the shared protein components are dynamically exchangeable.
- Andrew Z. Lin
- , Kiersten M. Ruff
- & Rohit V. Pappu
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Article
| Open AccessInflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
The immune suppression required for the resolution of acute inflammation is characterised by molecular and metabolic reprogramming of myeloid cells. Authors here show that the transcription factor ZEB1 is a key mediator of the pathway governing transition from inflammation to immunosuppression via regulating mitochondrial translation in macrophages.
- Marlies Cortés
- , Agnese Brischetto
- & Antonio Postigo
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Article
| Open AccessAn adaptive stress response that confers cellular resilience to decreased ubiquitination
Hunt et al. identify the protein sets that are modulated by RNAi for each E2 ubiquitin-conjugating enzyme in human cells. By analyzing the UBA1/E2-sensitive proteome, they report an adaptive stress response that preserves peroxisomal protein import in cells with decreased ubiquitination capacity.
- Liam C. Hunt
- , Vishwajeeth Pagala
- & Fabio Demontis
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Article
| Open AccessCryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer