Featured
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| Open AccessPeroxisomal targeting of a protein phosphatase type 2C via mitochondrial transit
Import of proteins into specific cellular compartments is critical for organelle function and several proteins are known to be imported into multiple compartments. Here, the authors report that the protein Ptc5 is first sorted to and processed in the mitochondria before being targeted to peroxisomes, which may influence mitochondria-peroxisome interorganellar contact.
- Thorsten Stehlik
- , Marco Kremp
- & Johannes Freitag
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Article
| Open AccessIncreased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
- Maria Calvo-Rodriguez
- , Steven S. Hou
- & Brian J. Bacskai
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Article
| Open AccessDecoding the stoichiometric composition and organisation of bacterial metabolosomes
Enteric pathogens such as Salmonella depend on propanediol-utilising microcompartments (Pdu MCP), which self-assemble from cytosolic proteins. Using mass spectrometry-based absolute quantification, the authors here define the protein stoichiometry and propose an organizational model of a Salmonella Pdu MCP.
- Mengru Yang
- , Deborah M. Simpson
- & Lu-Ning Liu
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Article
| Open AccessKinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells
Kinesin-1 is a motor protein transporting cargo along microtubules. Here the authors show that kinesin-1 is required for antigen cross-presentation and coordinates endosome scission from early endosomes to allow sorting internalized cargoes towards the recycling endosomal or lysosomal compartments.
- Meriem Belabed
- , François-Xavier Mauvais
- & Gaël Ménasché
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Article
| Open AccessA salvage pathway maintains highly functional respiratory complex I
Maintenance and quality control of the mitochondrial respiratory chain complexes responsible for bulk energy production are unclear. Here, the authors show that the mitochondrial protease ClpXP is required for the rapid turnover of the core N-module of respiratory complex I, which happens independently of other modules in the complex.
- Karolina Szczepanowska
- , Katharina Senft
- & Aleksandra Trifunovic
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Article
| Open AccessMitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Small open reading frame-encoded peptides (SEPs), shorter than 100 amino acids, are involved in many cell biological processes. Here the authors identify 16 nuclear-encoded mitochondrial SEPs, including BRAWNIN, an essential regulator of respiratory chain complex III assembly and ATP production.
- Shan Zhang
- , Boris Reljić
- & Lena Ho
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Article
| Open AccessWounding triggers MIRO-1 dependent mitochondrial fragmentation that accelerates epidermal wound closure through oxidative signaling
Mitochondria are important organelles that generate and respond to signals to maintain cellular homeostasis. Here the authors show that wounding triggers GTPase MIRO-1- and calcium-dependent mitochondrial fragmentation, which aids tissue wound repair through cytochrome P450 and mitochondrial reactive oxygen species.
- Hongying Fu
- , Hengda Zhou
- & Suhong Xu
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Article
| Open AccessThe anti-viral dynamin family member MxB participates in mitochondrial integrity
Mx proteins belong to the dynamin family of large GTPases and are highly induced by interferon in virally infected cells. The authors show that uninfected immune cells and hepatocytes also express MxB protein that associates with mitochondria to alter the morphology and genome of this organelle.
- Hong Cao
- , E. W. Krueger
- & Mark A. McNiven
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Article
| Open AccessImpaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.
- Alessandro Luciani
- , Anke Schumann
- & Olivier Devuyst
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Article
| Open AccessREEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects
The sarcoplasmic (SR) and endoplasmic reticulum (ER) are involved in heart development but how this arises is unclear. Here, the authors show that loss of a SR/ER protein REEP5 causes membrane destabilization and decreased cardiac myocyte contractility, with cardiac dysfunction in mutant mouse and zebrafish models.
- Shin-Haw Lee
- , Sina Hadipour-Lakmehsari
- & Anthony O. Gramolini
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Article
| Open AccessSpatiotemporal contact between peroxisomes and lipid droplets regulates fasting-induced lipolysis via PEX5
Lipid droplets are organelles that regulate lipid metabolism but if organellar contacts play a role during lipolysis is unclear. Here, the authors show that peroxisomes and peroxisomal protein PEX5 play pivotal roles in the spatial and temporal regulation of fasting-induced lipolysis by translocating ATGL onto lipid droplets
- Jinuk Kong
- , Yul Ji
- & Jae Bum Kim
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Article
| Open AccessGolgi organization is regulated by proteasomal degradation
Correct Golgi assembly is important to cellular homeostasis but regulation of its structure under stress remains unclear. Here, the authors identify stress-induced degradation of GM130 by Golgi-localized 26S proteasomes, leading to Golgi dispersal.
- Avital Eisenberg-Lerner
- , Ron Benyair
- & Yifat Merbl
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Article
| Open AccessThe inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection
The influenza virus hemagglutinin (HA) protein is a target for antivirals. Here, using a multivalent peptide library screen, the authors identify PVF-tet as an HA inhibitor and show that the peptide inhibits IAV replication by sequestering HA into amphisomes, suggesting these to represent a type of anti-viral machinery.
- Jumpei Omi
- , Miho Watanabe-Takahashi
- & Kiyotaka Nishikawa
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Article
| Open AccessCSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence
Senescence of metabolically active cells is a process linked to ageing. Here the authors reveal that CSB is required to block replicative senescence, and epigenetic control of CSB downregulation triggers proliferative arrest in a p21-dependent manner.
- Clément Crochemore
- , Cristina Fernández-Molina
- & Miria Ricchetti
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Article
| Open AccessSIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals
There is growing evidence that autophagy might serve specialized functions in neurons besides its role in protein homeostasis. In this study, authors demonstrate that axonal retrograde transport of BDNF/TrkB in neuronal amphisomes is involved in plasticity-relevant local signaling at presynaptic boutons and that SIPA1L2, a member of the SIPA1L family of neuronal RapGAPs, associates via LC3b to TrkB-containing amphisomes to regulate its motility and signaling at the axon terminals
- Maria Andres-Alonso
- , Mohamed Raafet Ammar
- & Michael R. Kreutz
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Article
| Open AccessEvidence that cyanobacterial Sll1217 functions analogously to PGRL1 in enhancing PGR5-dependent cyclic electron flow
In Arabidopsis, PGR5 and PGRL1 heterodimers enable cyclic electron flow to safeguard photosystem I during high light intensity. Here, the authors provide evidence that cyanobacteria, while lacking an obvious PGRL1 homologue, use an analogous PGRL1-like protein to facilitate cyclic electron flow.
- Marcel Dann
- & Dario Leister
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Article
| Open AccessDynamic constriction and fission of endoplasmic reticulum membranes by reticulon
The endoplasmic reticulum (ER) is an intracellular network characterized by highly dynamic behavior whose control mechanisms are unclear. Here, the authors show that the ER-membrane protein Reticulon (Rtnl1) can constrict ER bilayers and lead to ER fission.
- Javier Espadas
- , Diana Pendin
- & Andrea Daga
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Article
| Open AccessPlant AtEH/Pan1 proteins drive autophagosome formation at ER-PM contact sites with actin and endocytic machinery
Arabidopsis EH/Pan1 proteins are part of the TPLATE complex (TPC) that is required for endocytosis in plants. Here, the authors show AtEH/Pan1 proteins also act in actin-mediated autophagy, by interacting with VAP27-1 at ER-PM contact sites and recruiting TPLATE and AP-2 complex subunits, clathrin and ARP2/3/ proteins to autophagosomes.
- Pengwei Wang
- , Roman Pleskot
- & Patrick J. Hussey
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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 AccessStructural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset
Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Here, authors report crystal structures of truncated human MFN2 in different nucleotide-loading states and show that MFN2 forms sustained dimers even after GTP hydrolysis.
- Yu-Jie Li
- , Yu-Lu Cao
- & Song Gao
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Article
| Open AccessHydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
Hydralazine is a drug used in the treatment of heart failure and cancer, and it has recently been shown to promote lifespan in C. elegans. Here, the authors elucidate the mechanism of action of hydralazine, and show that it targets PKA to promote mitochondrial function via Sirtuin1/5.
- Esmaeil Dehghan
- , Mohammad Goodarzi
- & Hamid Mirzaei
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Article
| Open AccessMiro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery
Mitochondrial cristae organization and ER-mitochondria contact sites are critical structures for cellular function. Here, the authors use super-resolution microscopy to show that Miro GTPases form clusters required for normal ER-mitochondria contact sites formation and to link cristae organization to the mitochondrial transport machinery.
- Souvik Modi
- , Guillermo López-Doménech
- & Josef T. Kittler
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Article
| Open AccessLinkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Lipid nanoparticles (LNPs) are potential platforms for RNA-based therapeutics, but the fate of LNP-RNAs upon internalization into the cell is unclear. Here, the authors show that LNP-mRNAs and ionizable lipids escape the endosomes and are re-released via extracellular vesicles which could deliver the functional mRNA to other cells.
- Marco Maugeri
- , Muhammad Nawaz
- & Hadi Valadi
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Article
| Open AccessRan pathway-independent regulation of mitotic Golgi disassembly by Importin-α
Golgi disassembly is required for mitosis and occurs by vesicle fusion suppression, although the mechanism is unclear. Here, Chang et al. show, with quantitative analyses and crystallography, that Importin-α regulates this process by blocking GM130-p115 interactions in a Ran pathway-independent way.
- Chih-Chia Chang
- , Ching-Jou Chen
- & Kuo-Chiang Hsia
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Article
| Open AccessNPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
Though endocytosed dietary cholesterol is transferred to the endoplasmic reticulum (ER), how this is regulated is unclear. Here, the authors report a role for Niemann-Pick Type C Protein 1 (NPC1) in tethering endocytic organelles to the ER, which may contribute to interorganelle cholesterol transport.
- D. Höglinger
- , T. Burgoyne
- & E. R Eden
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Article
| Open AccessA lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites
Plasmodium and Toxoplasma parasites rely on rhoptry exocytosis for invasion, but the underlying mechanism is not known. Here, Suarez et al. characterize rhoptry apical surface proteins (RASP) that localize to the rhoptry cap and bind charged lipids, and are essential for rhoptry secretion and invasion.
- Catherine Suarez
- , Gaëlle Lentini
- & Maryse Lebrun
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Article
| Open AccessAn electrostatic switching mechanism to control the lipid transfer activity of Osh6p
Osh6p and Osh7p are yeast lipid transfer proteins (LTPs) that must transiently interact with membranes but how they escape from the electrostatic attraction of the plasma membrane is unclear. Here authors show that Osh6p reduces its avidity for anionic membranes once it captures PS or PI4P, due to a molecular lid closing its lipid-binding pocket.
- Nicolas-Frédéric Lipp
- , Romain Gautier
- & Guillaume Drin
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Article
| Open AccessImpaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease
Dysregulation of intracellular calcium is reported in Alzheimer’s disease. Here the authors show that loss of the mitochondrial Na+ /Ca2+ exchanger, NCLX – primary route of mitochondrial calcium efflux, precedes neuronal pathology in experimental models and contributes to Alzheimer’s disease progression.
- Pooja Jadiya
- , Devin W. Kolmetzky
- & John W. Elrod
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Article
| Open AccessIn vitro fusion of single synaptic and dense core vesicles reproduces key physiological properties
Regulated exocytosis of neuronal synaptic vesicles is substantially faster than that of endocrine dense core vesicles despite similar molecular machineries. Here authors compare SNARE-mediated fusion of purified synaptic vesicles with insulin vesicles and see disparities in calcium-triggered fusion rates.
- Alex J. B. Kreutzberger
- , Volker Kiessling
- & Lukas K. Tamm
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Article
| Open AccessIP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer
Membrane contact sites between the ER and mitochondria are known to convey calcium signals between these two organelles via IP3 receptors, but the molecular mechanisms are currently unclear. Here, the authors show that IP3 receptors play a structural tethering role in maintaining ER-mitochondrial contacts.
- Adam Bartok
- , David Weaver
- & György Hajnóczky
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Article
| Open AccessMICU1 controls cristae junction and spatially anchors mitochondrial Ca2+ uniporter complex
Proper mitochondrial structure is critical for normal function. Here, the authors show with SIM that the mitochondrial Ca2+ uniporter complex and localization of component MICU1 is critical to maintaining cristae junction stability and overall mitochondrial membrane structure.
- Benjamin Gottschalk
- , Christiane Klec
- & Wolfgang F. Graier
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Article
| Open AccessMul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts
Little is known about the pathways that maintain mitochondrial structure and function under neuronal stress conditions. Here, authors demonstrate that the Mul1-Mfn2 pathway plays a checkpoint role in maintaining mitochondrial integrity and energy maintenance by ensuring ER-mitochondrial tethering and preventing mitophagy.
- Rajat Puri
- , Xiu-Tang Cheng
- & Zu-Hang Sheng
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Article
| Open AccessLysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export
Cholesterol transport is tightly regulated in the cell and in lysosomes is regulated by NPC1/2. Here, Heybrock et al. use molecular modeling, knockout mice and cell based studies to show that LIMP-2 also mediates lysosomal cholesterol transport.
- Saskia Heybrock
- , Kristiina Kanerva
- & Dante Neculai
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Article
| Open AccessDegron-tagged reporters probe membrane topology and enable the specific labelling of membrane-wrapped structures
Visualising certain organelles and their dynamics is challenging in living cells. Here the authors co-opt selective degradation to label membrane-bound compartments in worm embryos and mammalian cells, revealing membrane topology during cell division.
- Katharina B. Beer
- , Gholamreza Fazeli
- & Ann M. Wehman
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Article
| Open AccessMitofusins regulate lipid metabolism to mediate the development of lung fibrosis
Mitochondria of alveolar type 2 epithelial cells (AEC2) in the lung have been suggested to play a role in the development of idiopathic pulmonary fibrosis (IPF). Here the authors show that loss of mitofusin1 and mitofusin2 in murine AEC2 cells leads to the development of lung fibrosis through the regulation of surfactant lipids.
- Kuei-Pin Chung
- , Chia-Lang Hsu
- & Augustine M. K. Choi
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Article
| Open AccessKLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants
Cytochrome P450 oxidases (CYPs) are enzymes that participate in the xenobiotic detoxification and their expression is enhanced in long-lived model organisms. Here the authors show that KLF-1 promotes cyp expression and ensures lifespan extension in C. elegans mitomutants by activating mitohormesis.
- Marija Herholz
- , Estela Cepeda
- & Aleksandra Trifunovic
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Article
| Open AccessRNA is a critical element for the sizing and the composition of phase-separated RNA–protein condensates
RNA promotes liquid-liquid phase separation and contributes to the ribonucleoprotein granule assembly. Here the authors employ the protein scaffold ArtiGranule and show the role of intracellular RNA in nucleation and sizing of the phase separated condensates.
- Marina Garcia-Jove Navarro
- , Shunnichi Kashida
- & Zoher Gueroui
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Article
| Open AccessAdult stem cell deficits drive Slc29a3 disorders in mice
Mutations in equilibrative nucleoside transporter 3 (ENT3), encoded by SLC29A3, cause a spectrum of human genetic disorders. Here, the authors show altered haematopoietic stem cell and mesenchymal stem cell fates in ENT3-deficient mice, due to misregulation of the AMPK-mTOR-ULK axis.
- Sreenath Nair
- , Anne M. Strohecker
- & Rajgopal Govindarajan
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Article
| Open AccessDietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain
Lipid droplets (LDs) are fat storage organelles that are initiated and expanded by seipins at ER contact sites. Here the authors show that the C. elegans seipin ortholog SEIP-1 is recruited to these sites by certain dietary fatty acids to support the expansion of a subset of LDs.
- Zhe Cao
- , Yan Hao
- & Ho Yi Mak
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Article
| Open AccessOxidative post-translational modification of EXECUTER1 is required for singlet oxygen sensing in plastids
Singlet oxygen generated by photosynthesis under photo-oxidative stress conditions triggers retrograde signaling from plastids to nuclei. Here, the authors show that singlet oxygen perception and subsequent signaling events require oxidative post-translational modification of the EXECUTER1 protein.
- Vivek Dogra
- , Mingyue Li
- & Chanhong Kim
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Article
| Open AccessNCP activates chloroplast transcription by controlling phytochrome-dependent dual nuclear and plastidial switches
Phytochrome signaling in the nucleus can activate expression of photosynthesis-associated genes in plastids. Here Yang et al. show that NCP is a dual-targeted protein that promotes phytochrome B localization to photobodies in the nucleus while facilitating PEP polymerase assembly in the plastids.
- Emily J. Yang
- , Chan Yul Yoo
- & Meng Chen
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Article
| Open AccessPhytochrome activates the plastid-encoded RNA polymerase for chloroplast biogenesis via nucleus-to-plastid signaling
Light initiates chloroplast biogenesis by controlling gene expression in plastids. Here Yoo et al. show that nuclear phytochrome signaling triggers plastid gene expression via a novel dual-localized protein necessary for nuclear phytochrome signaling and subsequent anterograde signaling to the plastid.
- Chan Yul Yoo
- , Elise K. Pasoreck
- & Meng Chen
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Article
| Open AccessSTX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism
Mitophagy plays a critical role in cellular homeostasis, and PINK1/Parkin-mediated mitophagy is the most thoroughly characterized. Here, Xian et al. show that STX17 induces mitophagy via a macroautophagy pathway regulated by Fis1, by a PINK1/Parkin-independent route.
- Hongxu Xian
- , Qiaoyun Yang
- & Yih-Cherng Liou
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Article
| Open AccessNuclear membrane protein Lem2 regulates nuclear size through membrane flow
Nuclear size scales with cell size, but the underlying mechanisms are unclear. Here, the authors report in fission yeast that the inner nuclear membrane protein Lem2 and the ER membrane protein Lnp1 are barriers to membrane flow and propose that they maintain nuclear size in proportion to cell membrane content.
- Kazunori Kume
- , Helena Cantwell
- & Paul Nurse
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Article
| Open AccessSelf-organization of Plk4 regulates symmetry breaking in centriole duplication
During centriole duplication, Plk4 regulates formation of a single daughter centriole adjacent to the mother centriole, but the mechanism is unclear. Here, the authors show that Plk4 can undergo liquid–liquid phase separation and that the condensation properties are regulated by autophosphorylation.
- Shohei Yamamoto
- & Daiju Kitagawa
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Article
| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessSNAREs define targeting specificity of trafficking vesicles by combinatorial interaction with tethering factors
Intracellular vesicle targeting is mediated by Rab GTPases that cooperate with phosphatidylinositides and SNARE proteins, which then facilitate membrane fusion. Here, the authors microinject artificial vesicles into HeLa cells and find that SNAREs play a more prominent role in targeting specificity of trafficking vesicles than previously known.
- Seiichi Koike
- & Reinhard Jahn
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Article
| Open AccessFoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism
Insulin signaling represses Forkhead transcription factor FoxO activity, which contributes to organismal metabolism. Here, the authors use proteomics to identify positively regulated insulin signaling targets FoxK1/K2 and demonstrate their role in lipid metabolism and mitochondrial regulation.
- Masaji Sakaguchi
- , Weikang Cai
- & C. Ronald Kahn
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Article
| Open AccessPhosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc1 complex function
Phosphatidylethanolamine (PE) is synthesized by four separate pathways, although surprisingly, perturbing mitochondrial PE synthesis compromises mitochondrial function. Here, the authors show that mitochondrial PE synthesis is required for Complex III function and challenge PE trafficking dogma.
- Elizabeth Calzada
- , Erica Avery
- & Steven M. Claypool