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| 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 AccessPhosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome
The epidermal growth factor receptor (EGFR) plays important roles in cell growth and motility. Here, authors reveal an unexpected function for a metabolic enzyme PGK1 and advance the mechanistic understanding of lysosomal transport of EGFR.
- Shao-Ling Chu
- , Jia-Rong Huang
- & Jia-Wei Hsu
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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 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 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 AccessThe transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells
Type 1 conventional dendritic cells (cDC1) play a pivotal role in the cross-presentation of antigens, enabling efficient CD8 + T cell response. Here authors show that the transcription factor Zeb1 essentially regulates this process via facilitating the reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytoplasm.
- Yan Wang
- , Quan Zhang
- & Nengming Xiao
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Article
| Open AccessLysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization
Cystinosis is a lysosomal storage disease that affects the kidney. Here, the authors use preclinical models and advanced profiling techniques to discover the mechanism by which defective cystine mobilization from lysosomes disrupts kidney cell function, offering insights into potential therapies.
- Marine Berquez
- , Zhiyong Chen
- & Alessandro Luciani
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| Open AccessHypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion
Several organelle membranes make contact in the cell, with many contacts being spatially segregated sites dedicated to specific functions. Here, Hao et al. show that hypoxia increases mitochondria-lysosome contacts, leading to engulfment and degradation of the mitochondria.
- Tianshu Hao
- , Jianglong Yu
- & Zhiyin Song
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Article
| Open AccessLoss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation
CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation.
- Alessia Calcagni’
- , Leopoldo Staiano
- & Andrea Ballabio
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Article
| Open AccessApicobasal RNA asymmetries regulate cell fate in the early mouse embryo
How do cells of the preimplantation mouse embryo make decisions? Here the authors discovered that the spatial sorting of mRNAs, tRNA, rRNAs and organelles lead to localized translation, conducive for cell fate allocation and embryonic development.
- Azelle Hawdon
- , Niall D. Geoghegan
- & Jennifer Zenker
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| Open AccessMulti-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health
Daly, Danson and colleagues employ a multi-omic approach in neuroglioma cells to characterise endolysosomal dysfunction caused by perturbation of the evolutionarily conserved Retromer complex, highlighting Retromer’s neuroprotective function.
- James L. Daly
- , Chris M. Danson
- & Peter J. Cullen
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| Open AccessPhospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism
Phospholipase D3 polymorphisms are linked to late-onset Alzheimer’s disease but the mechanisms are not understood. Van Acker and colleagues show that Phospholipase D3 processes mitochondrial DNA in lysosomes to maintain lysosomal homeostasis and proper degradation of the amyloid precursor protein.
- Zoë P. Van Acker
- , Anika Perdok
- & Wim Annaert
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| Open AccessTargeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct
Mutations in glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Using a fusion protein comprising GCase and a transferrin receptor antibody fragment, the authors show that the transferrin receptor pathway can be therapeutically exploited to both pass the blood-brain barrier and efficiently target lysosomal GCase deficiency.
- Alexandra Gehrlein
- , Vinod Udayar
- & Ravi Jagasia
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Article
| Open AccessConformational cycle of human polyamine transporter ATP13A2
ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson’s disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle.
- Jianqiang Mu
- , Chenyang Xue
- & Zhongmin Liu
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Article
| Open AccessOrthodenticle homeobox 2 is transported to lysosomes by nuclear budding vesicles
Many homeodomain transcription factors are secreted and move to neighboring cells. Here, orthodenticle homeobox 2 is shown to be exported from the nucleus in a nuclear membrane, which buds off to then be degraded or secreted.
- Jun Woo Park
- , Eun Jung Lee
- & Jin Woo Kim
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Article
| Open AccessSugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.
- Pei Ying Ng
- , Amy B. P. Ribet
- & Nathan J. Pavlos
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Article
| Open AccessLysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism
Extensive lysosomal damage can result in cell death but how limited protease leakage affects cytoplasmic organelles in viable cells is not well understood. Here the authors show that limited lysosomal damage leads to changes in the mitochondrial proteome and the modulation of macrophage immunometabolism.
- Claudio Bussi
- , Tiaan Heunis
- & Maximiliano G. Gutierrez
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| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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| Open AccessCross-linking of the endolysosomal system reveals potential flotillin structures and cargo
Protein complexes play a decisive role for lysosomal function. Here, the authors use cross-linking mass spectrometry and integrative modeling to investigate lysosomes and early endosomes; characterizing protein interactions, structures, and the cargo of flotillin-mediated endocytosis.
- Jasjot Singh
- , Hadeer Elhabashy
- & Dominic Winter
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| Open AccessSpatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
Methods to assess organellar content are important. Here, Park et al develop a method for rapid isolation of early/sorting endosomes and demonstrate the application of the approach for analysis of endosomal proteomes and lipidomes, and for analysis of APP processing to Aβ via β and γ-Secretases.
- Hankum Park
- , Frances V. Hundley
- & J. Wade Harper
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Article
| Open AccessGCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway
Lysosomal biogenesis errors often result in diseases including mucolipidosis. Here Zhang and Yang et al. identify TMEM251/GCAF as a mannose-6-phosphate modification regulator that is necessary for correct lysosomal targeting, and classify Mucolipidosis Type V as resulting from GCAF mutations.
- Weichao Zhang
- , Xi Yang
- & Ming Li
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| Open AccessBidirectional lysosome transport: a balancing act between ARL8 effectors
Most organelles move bidirectionally on microtubule tracks, yet how this opposing movement is regulated by kinesin and dynein remains unclear. Recent work found that ARL8, a known anterograde adaptor linking the lysosome to kinesin, also links lysosomes to the retrograde motor dynein, providing key insight into bidirectional organelle movement in cells.
- Agnieszka A. Kendrick
- & Jenna R. Christensen
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Article
| Open AccessLysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
Release of α-synuclein aggregates by neurons instigates spread of pathology in synucleinopathies, but the mechanism remains unclear. Here the authors show that neuronally generated α-synuclein aggregates accumulate within neuronal lysosomes and are released via SNARE-dependent lysosomal exocytosis.
- Ying Xue Xie
- , Nima N. Naseri
- & Manu Sharma
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| Open AccessDirect control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly
mTORC1 blocks lysosomal nutrient generation. Here, the authors show that mTORC1 inactivation triggers V-ATPase assembly, which rapidly initiates lysosomal acidification and degradation of protein contents throughout the lysosomal population.
- Edoardo Ratto
- , S. Roy Chowdhury
- & Wilhelm Palm
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Article
| Open AccessAAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1
Signaling via the mTOR complex 1 (mTORC1) maintains cellular and organismal homeostasis. Here the authors show that the AAA + ATPase Thorase binds mTOR to promote disassembly and inactivation of mTORC1 to fine tune TOR signaling according to amino acid availability.
- George K. E. Umanah
- , Leire Abalde-Atristain
- & Valina L. Dawson
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Article
| Open AccessSegregated cation flux by TPC2 biases Ca2+ signaling through lysosomes
TPC2 is a lysosomal ion channel permeable to both calcium and sodium ions. Here, the authors show that TPC2 can selectively increase its calcium permeability when simultaneously challenged by both its natural activators- NAADP and PI(3,5)P2.
- Yu Yuan
- , Dawid Jaślan
- & Sandip Patel
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Article
| Open AccessEfferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity
Efficient removal of apoptotic cells by phagocytosis underlies tissue development, wound repair, host defense and organ homeostasis. Here, authors identify TRPM7 as a regulator of cargo acidification and Ca2+ signaling during apoptotic cell clearance.
- Michael S. Schappe
- , Marta E. Stremska
- & Bimal N. Desai
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| Open AccessPhagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open AccessCa2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair
Activation of ESCRT prevents potentially lethal outcomes of minor perturbations in lysosomal integrity. Here authors show that Ca2 + -activated scrambling of sphingomyelin and its cytosolic turnover drives lysosomal repair independently of ESCRT.
- Patrick Niekamp
- , Felix Scharte
- & Joost C. M. Holthuis
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Article
| Open AccessQuantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification
mTORC1, central regulator of cell growth and autophagy suppressor, is activated on the lysosome surface, but its local role in lysosomal biology remains unclear. Here the authors show STK11IP is a substrate of mTORC1 that regulates lysosomal acidification through V-ATPase and represses autophagy.
- Zhenzhen Zi
- , Zhuzhen Zhang
- & Yonghao Yu
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Article
| Open AccessRUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin
Organellar transport is carefully regulated, and endolysosome localized ARL8 is important for kinesin recruitment and anterograde movement. Here, the authors show that RUFY3 and RUFY4 promote retrograde transport of endolysosomes by mediating interaction of ARL8 with dynein-dynactin.
- Tal Keren-Kaplan
- , Amra Sarić
- & Juan S. Bonifacino
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Article
| Open AccessRUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning
Lysosomes move along microtubule tracks, and Arl8b is known to stimulate their anterograde transport. Here, the authors identified RUFY3 as an Arl8b effector that interacts with dynein-dynactin to drive retrograde transport and perinuclear lysosome positioning.
- Gaurav Kumar
- , Prateek Chawla
- & Amit Tuli
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Article
| Open AccessIdentification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes
Cytotoxic T cells have specialised granules that are important for mediating their killing function. Here the authors characterise two types of cytotoxic granules and indicate different functions and temporal release of mediators at the immunological synapse.
- Hsin-Fang Chang
- , Claudia Schirra
- & Jens Rettig
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| Open AccessThe AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Targeted protein degradation is a promising approach for basic research and therapeutic applications. Here, the authors develop a targeted protein degradation platform called AUTOTAC to degrade oncoproteins and neurodegeneration-associated proteins via the p62-dependent autophagy-lysosome system.
- Chang Hoon Ji
- , Hee Yeon Kim
- & Yong Tae Kwon
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Article
| Open AccessAberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis
CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.
- Irene Lopez-Fabuel
- , Marina Garcia-Macia
- & Juan P. Bolaños
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Article
| Open AccessLung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.
- Barbara Spix
- , Elisabeth S. Butz
- & Christian Grimm
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Article
| Open AccessmTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation
Autophagy relies on coordinated fusion of organelle membranes, although the interplay between the regulatory machinery is not well studied. Here, the authors show that SNARE complex formation is inhibited by mTORC1 phosphorylation of VAMP8, which prevents autophagosome-lysosome fusion.
- Hong Huang
- , Qinqin Ouyang
- & Rong Liu
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Article
| Open AccessORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division
Membrane contact sites between organelles have specialized functions that are only beginning to be understood. Here, the authors show that ORP1L mediates lysosome recruitment and PI(4)P signaling at endoplasmic reticulum-lysosome-mitochondria three-way contact sites involved in mitochondrial division.
- Maxime Boutry
- & Peter K. Kim
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Article
| Open AccessSNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum
Endoplasmic reticulum (ER)-interorganelle membrane contact sites have emerged as key regulators of organelle dynamics. Here, the authors report that the ER-resident protein SNX19 mediates ER-endolysosome membrane contacts to maintain the perinuclear distribution of endolysosomes and restrict their motility.
- Amra Saric
- , Spencer A. Freeman
- & Juan S. Bonifacino
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Article
| Open AccessTSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Tuberous sclerosis complex (TSC) is a multiorgan disease that can lead to hyperactive mTORC1 due to deficient TSC1 or TSC2 protein function. Here, the authors find that despite high mTORC1 activity, TFEB localizes to the nucleus and drives lysosomal gene expression via a non-canonical Rag-dependent mechanism.
- Nicola Alesi
- , Elie W. Akl
- & Elizabeth P. Henske
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Article
| Open AccessStructural basis for the ARF GAP activity and specificity of the C9orf72 complex
C9orf72:SMCR8:WDR41 complex has been reported to have GAP activity for both ARF family proteins and the RAB proteins RAB8A and RAB11A. Here the authors provide structural and biochemical evidence for a specific function of the C9orf72 complex as an ARF GAP, and a structural framework for the GAP activity of the longin-containing GAP family.
- Ming-Yuan Su
- , Simon A. Fromm
- & James H. Hurley
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Article
| Open AccessDysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease
Mitochondria-lysosome contact sites mediate cross-talk between the two organelles. Here, the authors show mitochondria-lysosome contacts are prolonged and defective in heterozygous mutant GBA1 neurons, which is caused by defective modulation of TBC1D15 due to decreased GBA1 activity.
- Soojin Kim
- , Yvette C. Wong
- & Dimitri Krainc
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Article
| Open AccessFacilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors
Mutations in ENT3, encoded by SLC29A3, result in anaemia and erythroid hypoplasia, suggesting roles in erythropoiesis. Here the authors show that ENT3 acts as a lysosomal bile acid transporter, and mutation compromises taurine conjugated bile acid transport in erythroid progenitors leading to ER stress, and anaemia.
- Avinash K. Persaud
- , Sreenath Nair
- & Rajgopal Govindarajan
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Article
| Open AccessSVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan
Valosin-Containing Protein (VCP) is linked to diverse degenerative diseases. Here, the authors show that Small VCP Interacting Protein (SVIP) recruits VCP to lysosomes, with gain and loss of SVIP muscle expression modifying neural degeneration, animal behaviour and lifespan.
- Alyssa E. Johnson
- , Brian O. Orr
- & Graeme W. Davis
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Article
| Open Accessp62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response
Liquid-liquid phase separation of p62/SQSTM1 has been previously described, although the significance in vivo remains unclear. Here the authors show p62 droplets contain ubiquitin, autophagy-related proteins and Keap1 to serve as platform of not only autophagosome formation but also Nrf2 activation.
- Shun Kageyama
- , Sigurdur Runar Gudmundsson
- & Masaaki Komatsu
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Article
| Open AccessA trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export
Lysosomes play an important role in cellular LDL-cholesterol uptake. Here, the authors perform a genome-wide genetic screen for cholesterol regulators and identify C18orf8 as a conserved subunit of a trimeric Rab7 GEF that controls LDL trafficking and NPC1-dependent lysosomal cholesterol export.
- Dick J. H. van den Boomen
- , Agata Sienkiewicz
- & Paul J. Lehner
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Article
| Open AccessCathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling
The lysosomal aspartic protease Cathepsin D (CTSD) is associated with breast cancer progression. Here the authors show that selective inactivation of CTSD in mammary epithelium delays tumor onset due to impaired mTORC1 signaling, but resumes malignant growth due to compensatory oncogenic pathways
- Stephanie Ketterer
- , Julia Mitschke
- & Thomas Reinheckel
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Article
| Open AccessThe natural function of the malaria parasite’s chloroquine resistance transporter
Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediates multidrug resistance, but its natural function remains unclear. Here, Shafik et al. show that PfCRT transports host-derived peptides of 4-11 residues but not other ions or metabolites, and that drug-resistance-conferring PfCRT mutants have reduced peptide transport.
- Sarah H. Shafik
- , Simon A. Cobbold
- & Rowena E. Martin
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Article
| Open AccessDstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway
Congenital scoliosis is a complex genetic disorder characterized by vertebral malformation. Here, the authors demonstrate that loss of dstyk leads to scoliosis in zebrafish due to dysregulated biogenesis of notochord vacuoles and that DSTYK is required for lysosome biogenesis through mTORC1 regulation.
- Xianding Sun
- , Yang Zhou
- & Lin Chen