Featured
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| Open AccessN-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis
In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
- Mausita Karmakar
- , Martin Minns
- & Eric Pearlman
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Article
| Open AccessMicroglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration
Microglia perform important supporting roles for neurons in the brain. Here, the authors show that microglia clear neuron-derived α-synuclein through selective autophagy (synucleinphagy) to prevent accumulation of misfolded α-synuclein and subsequent neurodegeneration in a mouse model of disease.
- Insup Choi
- , Yuanxi Zhang
- & Zhenyu Yue
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Article
| Open AccessAMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy
AMPK integrates information about a cell’s energy status to inform decisions about cellular processes, including autophagy. Here the authors identify cyclin Y as an AMPK substrate, which phosphorylates cyclin Y and promotes its interaction with CDK16 to stimulate autophagy.
- Marc Dohmen
- , Sarah Krieg
- & Jörg Vervoorts
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Article
| Open AccessFasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase
Fasting induces hepatic autophagy to preserve energy homeostasis. Here the authors report that fasting induced fibroblast growth factor 21 signalling induces autophagy by activating lysine-specific demethylase 6B, leading to histone demethylation mediated activation of autophagy genes.
- Sangwon Byun
- , Sunmi Seok
- & Jongsook Kim Kemper
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Article
| Open AccessMonitoring spatiotemporal changes in chaperone-mediated autophagy in vivo
Chaperone mediated autophagy (CMA) is selective but its activity in different tissue types has been unclear due to a lack of tools. Here, the authors generate transgenic mice expressing a CMA reporter that provides spatial and temporal in vivo data, uncovering differences in CMA in distinct tissues.
- S. Dong
- , C. Aguirre-Hernandez
- & A. M. Cuervo
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Article
| Open AccessTemporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk
Autophagy declines with age, yet it is unclear if restoration of autophagy extends lifespan. Here, the authors demonstrate in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis.
- Liam D. Cassidy
- , Andrew R. J. Young
- & Masashi Narita
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Article
| Open AccessPI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress
The primary cilium is required for the autophagic response to shear stress. Here, the authors show that PI3KC2α has a role in ciliogenesis and promotes local PI3P production upon shear stress to induce autophagy that is distinct from VPS34-driven starvation-induced autophagy.
- Asma Boukhalfa
- , Anna Chiara Nascimbeni
- & Etienne Morel
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Article
| Open AccessA mosquito salivary protein promotes flavivirus transmission by activation of autophagy
Mosquito saliva affects transmission of flaviviruses, but underlying mechanisms are incompletely understood. Here, the authors show that Aedes aegypti venom allergen-1 (AaVA-1) promotes dengue and Zika virus transmission by activating autophagy in host immune cells of the monocyte lineage.
- Peng Sun
- , Kaixiao Nie
- & Gong Cheng
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Article
| Open AccessSestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals
Ageing is associated with muscle atrophy, which negatively impacts quality of life. Here the authors show that expression of sestrins decreases during inactivity and that their overexpression prevents atrophy in mice via modulation of autophagy and protein degradation.
- Jessica Segalés
- , Eusebio Perdiguero
- & Pura Muñoz-Cánoves
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Article
| Open AccessRequirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress
The autophagy receptor p62 mediates the assembly and removal of ubiquitylated protein aggregates by forming p62 bodies. Here, the authors identify an acetylation-dependent mechanism that regulates formation and autophagic clearance of p62 bodies under nutrient-deficient conditions.
- Zhiyuan You
- , Wen-Xue Jiang
- & Wei Liu
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Article
| Open AccessSKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
Here, Gassen et al. show that S-phase kinase-associated protein 2 (SKP2) is responsible for lysine-48-linked poly-ubiquitination of beclin 1, resulting in its proteasomal degradation, and that inhibition of SKP2 enhances autophagy and reduces replication of MERS coronavirus.
- Nils C. Gassen
- , Daniela Niemeyer
- & Theo Rein
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Article
| Open AccessLATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function
The autophagic and Hippo pathways are both well characterized contributors to cancer. Here, Tang et al show that LATS1, but not LATS2, negatively regulates autophagy by promoting Beclin1 ubiquitination, which restricts lethal autophagy induced by sorafenib treatment in cancer cells.
- Fengyuan Tang
- , Ruize Gao
- & Gerhard Christofori
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| Open AccessThe autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy
While the cellular recycling process autophagy has been linked to aging, the impact of selective autophagy on lifespan remains unclear. Here Kumsta et al. show that the autophagy receptor p62/SQSTM1 is required for hormetic benefits and p62/SQSTM1 overexpression is sufficient to extend C. elegans lifespan and improve proteostasis.
- Caroline Kumsta
- , Jessica T. Chang
- & Malene Hansen
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Article
| Open AccessTRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway
It was known that prolonged TRMPL1 activation induces TFEB translocation and upregulates autophagic gene regulation. Here, the authors show that acute TRMPL1 activation also induces autophagy through VPS34 and by lysosomal calcium release independent of TFEB.
- A. Scotto Rosato
- , S. Montefusco
- & D. L. Medina
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Article
| Open AccessThe in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection
ISG15 is a ubiquitin-like modifier that can be upregulated in response to bacterial infections. Here, the authors use proteomics to identify endogenous ISGylation substrates in the liver of Listeria monocytogenes infected mice and show that ISGylation alters basal and infection-induced autophagy.
- Yifeng Zhang
- , Fabien Thery
- & Lilliana Radoshevich
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Article
| Open AccessNAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD+ depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.
- Evandro F. Fang
- , Yujun Hou
- & Vilhelm A. Bohr
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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 AccessAutophagy is inhibited by ubiquitin ligase activity in the nervous system
Despite growing interest in the role of autophagy in neurons, it remains unclear how this process is regulated, in particular, how autophagy is spatially restricted in subcellular compartments in neurons. In this study, the authors use an unbiased proteomic approach to show that the autophagy initiating kinase UNC-51/ULK and autophagosome formation are inhibited by the ubiquitin ligase RPM-1, and demonstrate that this interaction is within specific axonal compartments.
- Oliver Crawley
- , Karla J. Opperman
- & Brock Grill
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Article
| Open AccessA secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing
Decreased autophagy is a hallmark of ageing, but its inter-tissue regulation is poorly understood. Here, Zhou et al. identify mir-83 in C. elegans, which is transported across tissues and suppresses autophagy, contributing to age-related decline.
- Yifei Zhou
- , Xueqing Wang
- & Yidong Shen
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Article
| Open AccessSelective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites
Centrosomes drive mitotic spindle formation and chromosome segregation. Here, the authors show that centrosome stability is regulated by selective autophagic degradation of centriolar satellite components in a process they term doryphagy, connecting autophagy and chromosomal integrity.
- Søs Grønbæk Holdgaard
- , Valentina Cianfanelli
- & Francesco Cecconi
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| Open AccessCytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response
The autophagy protein p62 undergoes liquid-liquid phase separation but how this is regulated is unclear. Here, the authors report that the histone chaperone DAXX interacts with p62 in the cytoplasm to drive its phase separation.
- Yi Yang
- , Thea L. Willis
- & Shouqing Luo
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Article
| Open AccessWHAMM initiates autolysosome tubulation by promoting actin polymerization on autolysosomes
After autophagic cargo degradation, autolysosomes undergo a reformation process to recycle lysosomal membrane components. Here, Dai et al. demonstrate that the actin nucleation promoting factor WHAMM is required for autolysosome reformation by providing an actin scaffold to drive tubulation.
- Anbang Dai
- , Li Yu
- & Hong-Wei Wang
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Article
| Open AccessMYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat
Genes related to lysosomal and autophagic systems are transcriptionally regulated by the Mit/TFE family of transcription factors. Here the authors show that MYC, in association with HDACs, suppresses the expression of lysosomal and autophagy genes by competing with the Mit/TFE transcription factors for occupancy of their target gene promoters.
- Ida Annunziata
- , Diantha van de Vlekkert
- & Alessandra d’Azzo
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Article
| Open AccessStructure of Myosin VI/Tom1 complex reveals a cargo recognition mode of Myosin VI for tethering
Myosin VI can facilitate the maturation of autophagosomes in autophagy through interactions with Tom1 and autophagy receptors. Here authors report the structure of the cargobinding domain of Myosin VI in complex with Tom1, which provides insights into Myosin IV’s cargo recognition modes.
- Shichen Hu
- , Yujiao Guo
- & Lifeng Pan
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Article
| Open AccessIncreased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone
Osteoblasts mediate bone formation, and their differentiation requires expression of EphrinB2. Here, the authors show that EphrinB2 is also expressed by osteocytes, and that its genetic ablation in mice is associated with altered autophagy, elevated mineralization and brittle bone.
- Christina Vrahnas
- , Martha Blank
- & Natalie A. Sims
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Article
| Open AccessLysosomal degradation of newly formed insulin granules contributes to β cell failure in diabetes
Impaired beta-cell insulin secretion is a key pathological feature of type 2 diabetes. Here, the authors describe metabolic stress induced lysosomal degradation of newly formed insulin granules, independent of macroautophagy, as a potential mechanism for beta-cell dysfunction.
- Adrien Pasquier
- , Kevin Vivot
- & Romeo Ricci
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Article
| Open AccessmTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4
Denervation leads to muscle atrophy and neuromuscular endplate remodeling. Here, the authors show that a balanced activation of mTORC1 contributes to the dynamic regulation of autophagic flux in denervated muscle and that activation of PKB/Akt promotes the nuclear import of HDAC4, which is essential for endplate maintenance upon nerve injury
- Perrine Castets
- , Nathalie Rion
- & Markus A. Rüegg
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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 AccessDRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca2+ homeostasis and cellular stress responses.
- Giulia Favaro
- , Vanina Romanello
- & Marco Sandri
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Article
| Open AccessCurvature induction and membrane remodeling by FAM134B reticulon homology domain assist selective ER-phagy
FAM134B/RETREG1 is a selective ER-phagy receptor that regulates the size and shape of the endoplasmic reticulum. Here authors use molecular modeling and molecular dynamics simulations to assemble a structural model for the reticulon-homology domain of FAM134B.
- Ramachandra M. Bhaskara
- , Paolo Grumati
- & Gerhard Hummer
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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 AccessMolecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins
Autophagy adaptors and receptors contain LC3-interacting region (LIR) motifs that bind selectively to the LIR docking site of GABARAP and other members of the ATG8 family. Here the authors show that in addition to the LIR motif also the region C-terminal of it is important for the binding specificity of both the centriolar satellite protein PCM1 and the ULK1 complex to GABARAP subfamily proteins.
- Martina Wirth
- , Wenxin Zhang
- & Stéphane Mouilleron
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Article
| Open AccessPhysical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis
Maintaining the intestinal barrier function requires a balance of multiple signalling pathways. Here the authors show that A20, an anti-inflammatory and anti-apoptotic protein, and Atg1611, an autophagy regulator, cross-regulate their respective protein levels and function to serve compensatory and redundant roles in fine-tuning gut barrier homeostasis.
- Karolina Slowicka
- , Inmaculada Serramito-Gómez
- & Geert van Loo
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Article
| Open AccessTranscriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance
The relationship between autophagy and BRAF signalling is unclear. Here, the authors describe that BRAF inhibition induces the autophagy-lysosomal function in BRAF-mutant melanomas via modulation of the TFEB and ZKSCAN3 transcriptome, which downregulates TGF-β and suppresses melanoma progression.
- Shun Li
- , Ying Song
- & Chengyu Liang
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Article
| Open AccessThe class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα
Peroxisome Proliferator Activated Receptor alpha (PPARα) drives fatty acid catabolism. Here, the authors show that in liver of autophagy deficient class 3 phosphoinositide 3-kinase mutant mice PPARα transcriptional repressors fail to degrade in lysosomes and accumulate leading to PPARα inhibition and blunted transcriptional responses during fasting.
- Anton Iershov
- , Ivan Nemazanyy
- & Ganna Panasyuk
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Article
| Open AccessReversible induction of mitophagy by an optogenetic bimodular system
Autophagic degradation of mitochondria (mitophagy) is a key quality control mechanism in cellular homeostasis, and its misregulation is involved in neurodegenerative diseases. Here the authors develop an optogenetic system for reversible induction of mitophagy and validate its use in cell culture and zebrafish embryos.
- Pasquale D’Acunzo
- , Flavie Strappazzon
- & Francesco Cecconi
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Article
| Open AccessCrizotinib-induced immunogenic cell death in non-small cell lung cancer
Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.
- Peng Liu
- , Liwei Zhao
- & Guido Kroemer
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Article
| Open AccessUSP8 maintains embryonic stem cell stemness via deubiquitination of EPG5
Autophagy is implicated in self-renewal of stem cells, including embryonic stem cells (ES cells). Here the authors demonstrate EPG5 is highly expressed in ES cells, and its deubiquitylation by USP8 stimulates its interaction with LC3 to promote autophagy and maintenance of stemness.
- Haifeng Gu
- , Xingxing Shi
- & Tongbiao Zhao
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Article
| Open AccessOmegasome-proximal PtdIns(4,5)P2 couples F-actin mediated mitoaggregate disassembly with autophagosome formation during mitophagy
Autophagic cells coordinate substrate remodeling with sequestration during autophagosome formation. Here, the authors show that during Parkin-mediated mitophagy, mitochondria are disassembled into progressively smaller aggregates near autophagy initiation sites in a PtdIns(4,5)P2-dependent manner.
- Cheng-Wei Hsieh
- & Wei Yuan Yang
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Article
| Open AccessSuppression of autophagic activity by Rubicon is a signature of aging
Autophagic activity decreases with age via unknown mechanisms. Here the authors show that expression of the negative autophagy regulator Rubicon increases with age, that its genetic ablation improves lifespan and ameliorates a number of age-associated phenotypes in invertebrates and in mouse models.
- Shuhei Nakamura
- , Masaki Oba
- & Tamotsu Yoshimori
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Article
| Open AccessThe flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species
Although ageing is the most important risk factor for chronic ailments, effective interventions remain rare. Here, the authors identify the flavonoid 4,4’-dimethoxychalcone and demonstrate that it extends lifespan and promotes health in multiple organisms by inducing autophagy.
- Didac Carmona-Gutierrez
- , Andreas Zimmermann
- & Frank Madeo
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Article
| Open AccessGigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production
Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover.
- Aurora Scrivo
- , Patrice Codogno
- & Pascale Bomont
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Article
| Open AccessKDEL receptor regulates secretion by lysosome relocation- and autophagy-dependent modulation of lipid-droplet turnover
Inter-organelle signaling coordinates adaptive responses via currently unknown mechanisms. Here, Tapia et al. show that KDEL signaling repositions lysosomes in a complex process termed ‘traffic-induced degradation response for secretion’ (TIDeRS) that connects multiple pathways and Golgi secretion.
- Diego Tapia
- , Tomás Jiménez
- & Jorge Cancino
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Article
| Open AccessLC3/GABARAPs drive ubiquitin-independent recruitment of Optineurin and NDP52 to amplify mitophagy
Selective autophagy receptors are thought to selectively recruit Atg8 positive membranes to cargo via their LIR motif. Here, the authors show the LIR motifs in OPTN and NDP52 are dispensable for selectivity, functioning instead to recruit additional receptors and amplify mitophagy.
- Benjamin Scott Padman
- , Thanh Ngoc Nguyen
- & Michael Lazarou
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Article
| Open AccessAutophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap
Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.
- Youngmin A. Lee
- , Luke A. Noon
- & Scott L. Friedman
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Article
| Open AccessSrc regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction
The growth-promoting activity of mTORC1 is regulated by amino acid availability via the Rag GTPases. Here, the authors demonstrate Src-dependent control of cell size and autophagy through disruption of the Rag GTPase–GATOR1 complex and mTORC1 activation at the lysosomal surface.
- Rituraj Pal
- , Michela Palmieri
- & Marco Sardiello
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Article
| Open AccessHarnessing copper-palladium alloy tetrapod nanoparticle-induced pro-survival autophagy for optimized photothermal therapy of drug-resistant cancer
“Conventional chemotherapy-photothermal therapy combination has limited efficacy in drug resistant cancers. Here they develop Copper-palladium tetrapod nanoparticles to overcome these challenges and show them to work in synergy with autophagy inhibitors to treat drug resistant cancers”
- Yunjiao Zhang
- , Rui Sha
- & Long-ping Wen
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Article
| Open AccessProbing aggrephagy using chemically-induced protein aggregates
Autophagic clearance of aggregates, aggrephagy, is essential for cellular homeostasis but tools to induce and monitor it are limited. Here the authors present a fluorescence-based aggrephagy induction assay to study spatiotemporal dynamics and control mechanisms driving protein aggregate clearance.
- Anne F. J. Janssen
- , Eugene A. Katrukha
- & Lukas C. Kapitein
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Article
| Open AccessGABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in neuronal systems, but the potential role for such neurotransmitters on the immune system are emerging. Here the authors show GABA signaling is linked to autophagy, enhancing the host response against intracellular bacteria.
- Jin Kyung Kim
- , Yi Sak Kim
- & Eun-Kyeong Jo