Lysosomal positioning coordinates cellular nutrient responses.

Abstract:

:mTOR (mammalian target of rapamycin) signalling and macroautophagy (henceforth autophagy) regulate numerous pathological and physiological processes, including cellular responses to altered nutrient levels. However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles intimately involved both in the activation of mTOR complex 1 (mTORC1) signalling and in degrading autophagic substrates. Here we report that lysosomal positioning coordinates anabolic and catabolic responses with changes in nutrient availability by orchestrating early plasma-membrane signalling events, mTORC1 signalling and autophagy. Activation of mTORC1 by nutrients correlates with its presence on peripheral lysosomes that are physically close to the upstream signalling modules, whereas starvation causes perinuclear clustering of lysosomes, driven by changes in intracellular pH. Lysosomal positioning regulates mTORC1 signalling, which in turn influences autophagosome formation. Lysosome positioning also influences autophagosome-lysosome fusion rates, and thus controls autophagic flux by acting at both the initiation and termination stages of the process. Our findings provide a physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Korolchuk VI,Saiki S,Lichtenberg M,Siddiqi FH,Roberts EA,Imarisio S,Jahreiss L,Sarkar S,Futter M,Menzies FM,O'Kane CJ,Deretic V,Rubinsztein DC

doi

10.1038/ncb2204

subject

Has Abstract

pub_date

2011-04-01 00:00:00

pages

453-60

issue

4

eissn

1465-7392

issn

1476-4679

pii

ncb2204

journal_volume

13

pub_type

杂志文章
  • Milk makes lysosomes lethal.

    abstract::Stat3 has been shown to regulate lysosome membrane permeabilization and cell death in vivo during post-lactation mammary gland involution. It is now revealed that Stat3 induces lysosome membrane permeabilization by causing phagocytosis of milk fat globules, which destabilize the lysosome membrane leading to leakage of...

    journal_title:Nature cell biology

    pub_type: 评论,杂志文章

    doi:10.1038/ncb3059

    authors: Krishna S,Overholtzer M

    更新日期:2014-11-01 00:00:00

  • Motor-free mitochondrial presequence translocase drives membrane integration of preproteins.

    abstract::The mitochondrial inner membrane is the central energy-converting membrane of eukaryotic cells. The electrochemical proton gradient generated by the respiratory chain drives the ATP synthase. To maintain this proton-motive force, the inner membrane forms a tight barrier and strictly controls the translocation of ions....

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1635

    authors: van der Laan M,Meinecke M,Dudek J,Hutu DP,Lind M,Perschil I,Guiard B,Wagner R,Pfanner N,Rehling P

    更新日期:2007-10-01 00:00:00

  • p53 mutations promote proteasomal activity.

    abstract::p53 mutations occur very frequently in human cancer. Besides abrogating the tumour suppressive functions of wild-type p53, many of those mutations also acquire oncogenic gain-of-function activities. Augmentation of proteasome activity is now reported as a common gain-of-function mechanism shared by different p53 mutan...

    journal_title:Nature cell biology

    pub_type: 新闻

    doi:10.1038/ncb3392

    authors: Oren M,Kotler E

    更新日期:2016-07-27 00:00:00

  • GENERATIVE CELL SPECIFIC 1 is essential for angiosperm fertilization.

    abstract::The double fertilization process in angiosperms is based on the delivery of a pair of sperm cells by the pollen tube (the male gametophyte), which elongates towards an embryo sac (the female gametophyte) enclosing an egg and a central cell. Several studies have described the mechanisms of gametophyte interaction, and ...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1345

    authors: Mori T,Kuroiwa H,Higashiyama T,Kuroiwa T

    更新日期:2006-01-01 00:00:00

  • Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells.

    abstract::The cyclical protrusion and retraction of the leading edge is a hallmark of many migrating cells involved in processes such as development, inflammation and tumorigenesis. The molecular identity of the signalling mechanisms that control these cycles has remained unknown. Here, we used live-cell imaging of biosensors t...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb2231

    authors: Tkachenko E,Sabouri-Ghomi M,Pertz O,Kim C,Gutierrez E,Machacek M,Groisman A,Danuser G,Ginsberg MH

    更新日期:2011-06-01 00:00:00

  • Arabidopsis HT1 kinase controls stomatal movements in response to CO2.

    abstract::Guard cells, which form stomata in leaf epidermes, sense a multitude of environmental signals and integrate this information to regulate stomatal movements. Compared with the advanced understanding of light and water stress responses in guard cells, the molecular mechanisms that underlie stomatal CO(2) signalling have...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1387

    authors: Hashimoto M,Negi J,Young J,Israelsson M,Schroeder JI,Iba K

    更新日期:2006-04-01 00:00:00

  • A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly.

    abstract::TP53 (tumour protein 53) is one of the most frequently mutated genes in human cancer and its role during cellular transformation has been studied extensively. However, the homeostatic functions of p53 are less well understood. Here, we explore the molecular dependency network of TP53 through an RNAi-mediated synthetic...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb2264

    authors: Krastev DB,Slabicki M,Paszkowski-Rogacz M,Hubner NC,Junqueira M,Shevchenko A,Mann M,Neugebauer KM,Buchholz F

    更新日期:2011-06-05 00:00:00

  • Loss of nucleoplasmic LAP2alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation.

    abstract::Lamina-associated polypeptide (LAP) 2alpha is a chromatin-associated protein that binds A-type lamins. Mutations in both LAP2alpha and A-type lamins are linked to human diseases called laminopathies, but the molecular mechanisms are poorly understood. The A-type lamin-LAP2alpha complex interacts with and regulates ret...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1793

    authors: Naetar N,Korbei B,Kozlov S,Kerenyi MA,Dorner D,Kral R,Gotic I,Fuchs P,Cohen TV,Bittner R,Stewart CL,Foisner R

    更新日期:2008-11-01 00:00:00

  • The planar cell polarity effector Fuz is essential for targeted membrane trafficking, ciliogenesis and mouse embryonic development.

    abstract::The planar cell polarity (PCP) signalling pathway is essential for embryonic development because it governs diverse cellular behaviours, and 'core PCP' proteins, such as Dishevelled and Frizzled, have been extensively characterized. By contrast, the 'PCP effector' proteins, such as Intu and Fuz, remain largely unstudi...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1966

    authors: Gray RS,Abitua PB,Wlodarczyk BJ,Szabo-Rogers HL,Blanchard O,Lee I,Weiss GS,Liu KJ,Marcotte EM,Wallingford JB,Finnell RH

    更新日期:2009-10-01 00:00:00

  • Senescent cells harbour features of the cancer epigenome.

    abstract::Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bi...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb2879

    authors: Cruickshanks HA,McBryan T,Nelson DM,Vanderkraats ND,Shah PP,van Tuyn J,Singh Rai T,Brock C,Donahue G,Dunican DS,Drotar ME,Meehan RR,Edwards JR,Berger SL,Adams PD

    更新日期:2013-12-01 00:00:00

  • Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation.

    abstract::The heterogeneity of exosomal populations has hindered our understanding of their biogenesis, molecular composition, biodistribution and functions. By employing asymmetric flow field-flow fractionation (AF4), we identified two exosome subpopulations (large exosome vesicles, Exo-L, 90-120 nm; small exosome vesicles, Ex...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/s41556-018-0040-4

    authors: Zhang H,Freitas D,Kim HS,Fabijanic K,Li Z,Chen H,Mark MT,Molina H,Martin AB,Bojmar L,Fang J,Rampersaud S,Hoshino A,Matei I,Kenific CM,Nakajima M,Mutvei AP,Sansone P,Buehring W,Wang H,Jimenez JP,Cohen-Gould L,P

    更新日期:2018-03-01 00:00:00

  • Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation.

    abstract::Autophagy is a lysosome-based degradation pathway. During autophagy, lysosomes fuse with autophagosomes to form autolysosomes. Following starvation-induced autophagy, nascent lysosomes are formed from autolysosomal membranes through an evolutionarily conserved cellular process, autophagic lysosome reformation (ALR), w...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb2557

    authors: Rong Y,Liu M,Ma L,Du W,Zhang H,Tian Y,Cao Z,Li Y,Ren H,Zhang C,Li L,Chen S,Xi J,Yu L

    更新日期:2012-09-01 00:00:00

  • Nuclear mRNA on the move.

    abstract::Innovations in live-cell microscopy and single-molecule analysis have allowed a new direct view of nuclear messenger RNA dynamics. A new study extends previous analyses of mRNA-protein intranuclear transport and links this critical step to the kinetics of moving through nuclear pore complexes. Seeing nuclear mRNA on t...

    journal_title:Nature cell biology

    pub_type: 评论,杂志文章

    doi:10.1038/ncb0610-525

    authors: Noble KN,Wente SR

    更新日期:2010-06-01 00:00:00

  • Differential requirement for the dual functions of β-catenin in embryonic stem cell self-renewal and germ layer formation.

    abstract::Canonical Wnt signalling has been implicated in mouse and human embryonic stem cell (ESC) maintenance; however, its requirement is controversial. β-catenin is the key component in this highly conserved Wnt pathway, acting as a transcriptional transactivator. However, β-catenin has additional roles at the plasma membra...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb2260

    authors: Lyashenko N,Winter M,Migliorini D,Biechele T,Moon RT,Hartmann C

    更新日期:2011-06-19 00:00:00

  • Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles.

    abstract::Robust mechanisms to control cell proliferation have evolved to maintain the integrity of organ architecture. Here, we investigated how two critical proliferative pathways, Myc and E2f, are integrated to control cell cycles in normal and Rb-deficient cells using a murine intestinal model. We show that Myc and E2f1-3 h...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb3210

    authors: Liu H,Tang X,Srivastava A,Pécot T,Daniel P,Hemmelgarn B,Reyes S,Fackler N,Bajwa A,Kladney R,Koivisto C,Chen Z,Wang Q,Huang K,Machiraju R,Sáenz-Robles MT,Cantalupo P,Pipas JM,Leone G

    更新日期:2015-08-01 00:00:00

  • The actin cable is dispensable in directing dorsal closure dynamics but neutralizes mechanical stress to prevent scarring in the Drosophila embryo.

    abstract::The actin cable is a supracellular structure that embryonic epithelia produce to close gaps. However, the action of the cable remains debated. Here, we address the function of the cable using Drosophila dorsal closure, a paradigm to understand wound healing. First, we show that the actin cytoskeleton protein Zasp52 is...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb3421

    authors: Ducuing A,Vincent S

    更新日期:2016-11-01 00:00:00

  • p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation.

    abstract::Cancer cells use aerobic glycolysis preferentially for energy provision and this metabolic change is important for tumour growth. Here, we have found a link between the tumour suppressor p53, the transcription factor NF-kappaB and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKKalpha and I...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1724

    authors: Kawauchi K,Araki K,Tobiume K,Tanaka N

    更新日期:2008-05-01 00:00:00

  • Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation.

    abstract::Membrane association with mother centriole (M-centriole) distal appendages is critical for ciliogenesis initiation. How the Rab GTPase Rab11-Rab8 cascade functions in early ciliary membrane assembly is unknown. Here, we show that the membrane shaping proteins EHD1 and EHD3, in association with the Rab11-Rab8 cascade, ...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb3109

    authors: Lu Q,Insinna C,Ott C,Stauffer J,Pintado PA,Rahajeng J,Baxa U,Walia V,Cuenca A,Hwang YS,Daar IO,Lopes S,Lippincott-Schwartz J,Jackson PK,Caplan S,Westlake CJ

    更新日期:2015-03-01 00:00:00

  • Exocytosis of single chromaffin granules in cell-free inside-out membrane patches.

    abstract::In chromaffin cells, exocytosis of single granules and properties of the fusion pore--the first connection between vesicular lumen and extracellular space --can be studied by cell-attached patch amperometry, which couples patch-clamp capacitance measurements with simultaneous amperometric recordings of transmitter rel...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb956

    authors: Dernick G,Alvarez de Toledo G,Lindau M

    更新日期:2003-04-01 00:00:00

  • A role for phosphatidic acid in COPI vesicle fission yields insights into Golgi maintenance.

    abstract::Proteins essential for vesicle formation by the Coat Protein I (COPI) complex are being identified, but less is known about the role of specific lipids. Brefeldin-A ADP-ribosylated substrate (BARS) functions in the fission step of COPI vesicle formation. Here, we show that BARS induces membrane curvature in cooperatio...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1774

    authors: Yang JS,Gad H,Lee SY,Mironov A,Zhang L,Beznoussenko GV,Valente C,Turacchio G,Bonsra AN,Du G,Baldanzi G,Graziani A,Bourgoin S,Frohman MA,Luini A,Hsu VW

    更新日期:2008-10-01 00:00:00

  • Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase.

    abstract::The cyclin-dependent kinase inhibitor p27(Kip1) is degraded at the G0-G1 transition of the cell cycle by the ubiquitin-proteasome pathway. Although the nuclear ubiquitin ligase (E3) SCF(Skp2) is implicated in p27(Kip1) degradation, proteolysis of p27(Kip1) at the G0-G1 transition proceeds normally in Skp2(-/-) cells. ...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1194

    authors: Kamura T,Hara T,Matsumoto M,Ishida N,Okumura F,Hatakeyama S,Yoshida M,Nakayama K,Nakayama KI

    更新日期:2004-12-01 00:00:00

  • Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes.

    abstract::Neural Wiskott-Aldrich syndrome protein (N-WASP) and WAVE are members of a family of proteins that use the Arp2/3 complex to stimulate actin assembly in actin-based motile processes. By entering into distinct macromolecular complexes, they act as convergent nodes of different signalling pathways. The role of WAVE in g...

    journal_title:Nature cell biology

    pub_type: 信件

    doi:10.1038/ncb1304

    authors: Innocenti M,Gerboth S,Rottner K,Lai FP,Hertzog M,Stradal TE,Frittoli E,Didry D,Polo S,Disanza A,Benesch S,Di Fiore PP,Carlier MF,Scita G

    更新日期:2005-10-01 00:00:00

  • Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells.

    abstract::Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional β cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and β...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/s41556-018-0271-4

    authors: Nair GG,Liu JS,Russ HA,Tran S,Saxton MS,Chen R,Juang C,Li ML,Nguyen VQ,Giacometti S,Puri S,Xing Y,Wang Y,Szot GL,Oberholzer J,Bhushan A,Hebrok M

    更新日期:2019-02-01 00:00:00

  • Matrix geometry determines optimal cancer cell migration strategy and modulates response to interventions.

    abstract::The molecular requirements and morphology of migrating cells can vary depending on matrix geometry; therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. We present a model of cell motility that encompasses actin-polymerization-based protrusions, actomyosin contr...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb2775

    authors: Tozluoğlu M,Tournier AL,Jenkins RP,Hooper S,Bates PA,Sahai E

    更新日期:2013-07-01 00:00:00

  • Prion domains: sequences, structures and interactions.

    abstract::Mammalian and most fungal infectious proteins (also known as prions) are self-propagating amyloid, a filamentous beta-sheet structure. A prion domain determines the infectious properties of a protein by forming the core of the amyloid. We compare the properties of known prion domains and their interactions with the re...

    journal_title:Nature cell biology

    pub_type: 杂志文章,评审

    doi:10.1038/ncb1105-1039

    authors: Ross ED,Minton A,Wickner RB

    更新日期:2005-11-01 00:00:00

  • Ran stimulates spindle assembly by altering microtubule dynamics and the balance of motor activities.

    abstract::The guanosine tri-phosphatase Ran stimulates assembly of microtubule spindles. However, it is not known what aspects of the microtubule cytoskeleton are subject to regulation by Ran in mitosis. Here we show that Ran-GTP stimulates microtubule assembly by increasing the rescue frequency of microtubules three- to eightf...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/35060000

    authors: Wilde A,Lizarraga SB,Zhang L,Wiese C,Gliksman NR,Walczak CE,Zheng Y

    更新日期:2001-03-01 00:00:00

  • Intrinsic lattice formation by the ryanodine receptor calcium-release channel.

    abstract::Recent theoretical analysis of a model lattice of interacting transmembrane receptor proteins has indicated that such clustering in the membrane could provide a novel mechanism for regulating receptor signalling in cells. It has been calculated that cooperative interactions between receptors organized into a cluster, ...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/35023625

    authors: Yin CC,Lai FA

    更新日期:2000-09-01 00:00:00

  • Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells.

    abstract::Changes in phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II (RNAP) are associated with transcription initiation, elongation and termination. Sites of active transcription are generally characterized by hyperphosphorylated RNAP, particularly at Ser 2 residues, whereas inactive or poised genes m...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb1663

    authors: Stock JK,Giadrossi S,Casanova M,Brookes E,Vidal M,Koseki H,Brockdorff N,Fisher AG,Pombo A

    更新日期:2007-12-01 00:00:00

  • Determinants of molecular motor directionality.

    abstract::Work over the past two years has led to a breakthrough in our understanding of the molecular basis of the directionality of the kinesin motor proteins. This breakthrough has come first from the reversal of directionality of the kinesin-related motor Ncd, followed closely by the reversal of kinesin's directionality and...

    journal_title:Nature cell biology

    pub_type: 杂志文章,评审

    doi:10.1038/14113

    authors: Endow SA

    更新日期:1999-10-01 00:00:00

  • DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.

    abstract::Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints. Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation, but little is known about their roles in sig...

    journal_title:Nature cell biology

    pub_type: 杂志文章

    doi:10.1038/ncb884

    authors: Fernandez-Capetillo O,Chen HT,Celeste A,Ward I,Romanienko PJ,Morales JC,Naka K,Xia Z,Camerini-Otero RD,Motoyama N,Carpenter PB,Bonner WM,Chen J,Nussenzweig A

    更新日期:2002-12-01 00:00:00