bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2019‒12‒08
twenty papers selected by
Viktor Korolchuk
Newcastle University


  1. EMBO J. 2019 Dec 05. e102586
    Schäfer JA, Schessner JP, Bircham PW, Tsuji T, Funaya C, Pajonk O, Schaeff K, Ruffini G, Papagiannidis D, Knop M, Fujimoto T, Schuck S.
      ER-phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER-phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro-ER-phagy has been discovered, the molecules and mechanisms mediating micro-ER-phagy remain unknown. Here, we first show that micro-ER-phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1-Spo7 phosphatase complex and the ESCRT machinery as key components for micro-ER-phagy. Third, we demonstrate that macro- and micro-ER-phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that the ESCRT machinery directly functions in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro-ER-phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis.
    Keywords:  ESCRT machinery; endoplasmic reticulum; microautophagy; yeast
    DOI:  https://doi.org/10.15252/embj.2019102586
  2. Autophagy. 2019 Dec 03. 1-2
    Stavoe AKH, Holzbaur ELF.
      Macroautophagy/autophagy is implicated in age-dependent neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson, Huntington and Alzheimer diseases, suggesting that an age-related decline in neuronal autophagy may contribute to the onset of neurodegeneration. We identified a significant decline in the rate of axonal autophagosome formation in neurons cultured from aged mice, accompanied by a striking increase in the accumulation of autophagic structures with aberrant morphologies. Using live-cell microscopy, we identified the specific step in autophagosome formation that becomes impaired with age, focusing on the role of the phosphoinositide binding protein WIPI2. We determined that the dynamic and local phosphorylation of WIPI2 is a critical regulatory step in autophagosome biogenesis in neurons and that this step is specifically affected by aging. Together, these results provide new insights into the regulation of autophagosome biogenesis in neurons and delineate how autophagosome formation is affected by age. These observations also point to a potential new target for therapeutic intervention.
    Keywords:  Aging; WIPI2; autophagosome biogenesis; autophagy; macroautophagy; neurodegeneration; neuronal autophagy
    DOI:  https://doi.org/10.1080/15548627.2019.1695401
  3. Front Cell Dev Biol. 2019 ;7 292
    Finetti F, Capitani N, Baldari CT.
      Ciliated cells exploit a specific transport system, the intraflagellar transport (IFT) system, to ensure the traffic of molecules from the cell body to the cilium. However, it is now clear that IFT activity is not restricted to cilia-related functions. This is strikingly exemplified by the observation that IFT proteins play important roles in cells lacking a primary cilium, such as lymphocytes. Indeed, in T cells the IFT system regulates the polarized transport of endosome-associated T cell antigen receptors and signaling mediators during assembly of the immune synapse, a specialized interface that forms on encounter with a cognate antigen presenting cell and on which T cell activation and effector function crucially depend. Cellular degradation pathways have recently emerged as new extraciliary functions of the IFT system. IFT proteins have been demonstrated to regulate autophagy in ciliated cells through their ability to recruit the autophagy machinery to the base of the cilium. We have now implicated the IFT component IFT20 in another central degradation process that also controls the latest steps in autophagy, namely lysosome function, by regulating the cation-independent mannose-6-phosphate receptor (CI-MPR)-dependent lysosomal targeting of acid hydrolases. This involves the ability of IFT20 to act as an adaptor coupling the CI-MPR to dynein for retrograde transport to the trans-Golgi network. In this short review we will discuss the emerging roles of IFT proteins in cellular degradation pathways.
    Keywords:  T cell; autophagy; degradation pathways; intraflagellar transport; lysosome
    DOI:  https://doi.org/10.3389/fcell.2019.00292
  4. Autophagy. 2019 Dec 03. 1-3
    Cui Y, Parashar S, Ferro-Novick S.
      Endoplasmic reticulum (ER) homeostasis is maintained by the removal of misfolded ER proteins via different quality control pathways. Aggregation-prone proteins, including certain disease-linked proteins, are resistant to conventional ER degradation pathways and require other disposal mechanisms. Reticulophagy is a disposal pathway that uses resident autophagy receptors. How these receptors, which are dispersed throughout the ER network, target a specific ER domain for degradation is unknown. We recently showed in budding yeast, that ER stress upregulates the reticulophagy receptor, triggering its association with the COPII cargo adaptor complex, Sfb3/Lst1-Sec23 (SEC24C-SEC23 in mammals), to discrete sites on the ER. These domains are packaged into phagophores for degradation to prevent the accumulation of protein aggregates in the ER. This unconventional role for Sfb3/Lst1 is conserved in mammals and is independent of its role as a cargo adaptor on the secretory pathway. Our findings may have important therapeutic implications in protein-aggregation linked neurodegenerative disorders.
    Keywords:  Aggregation-prone protein degradation; COPII cargo adaptor; SEC24C-SEC23; Sfb3/Lst1-Sec23; reticulophagy receptor
    DOI:  https://doi.org/10.1080/15548627.2019.1699347
  5. J Mol Biol. 2019 Nov 28. pii: S0022-2836(19)30677-1. [Epub ahead of print]
    Valionyte E, Yang Y, Roberts SL, Kelly J, Lu B, Luo S.
      Huntington's disease is a monogenetic neurodegenerative disease, which serves as a model of neurodegeneration with protein aggregation. Autophagy has been suggested to possess a great value to tackle protein aggregation toxicity and neurodegenerative diseases. Current studies suggest that autophagy-endolysosomal pathways are critical for HD pathology. Here we review recent advancement in the studies of autophagy and selective autophagy relating Huntington's disease. Restoration of autophagy flux and enhancement of selective removal of mutant huntingtin/disease-causing protein would be effective approaches towards tackling HD as well as other similar neurodegenerative disorders.
    Keywords:  Autophagy; Huntington's disease; huntingtin; neurodegeneration; selective autophagy
    DOI:  https://doi.org/10.1016/j.jmb.2019.11.012
  6. Mol Cell Proteomics. 2019 Dec 02. pii: mcp.RA119.001785. [Epub ahead of print]
    Wei J, Leung K, Truillet C, Ruggero D, Wells J, Evans MJ.
      Aberrantly high mTORC1 signaling is a known driver of many cancers and human disorders, yet pharmacological inhibition of mTORC1 rarely confers durable clinical responses. To explore alternative therapeutic strategies, herein we conducted a proteomics survey to identify cell surface proteins upregulated by mTORC1. A comparison of the surfaceome from Tsc1-/- versus Tsc1+/+ mouse embryonic fibroblasts revealed 59 proteins predicted to be significantly overexpressed in Tsc1-/- cells. Further validation of the data in multiple mouse and human cell lines showed that mTORC1 signaling most dramatically induced the expression of the proteases neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). Functional studies showed that constitutive mTORC1 signaling sensitized cells to genetic ablation of NEP and APN, as well as the biochemical inhibition of APN.  In summary, these data show that mTORC1 signaling plays a significant role in the constitution of the surfaceome, which in turn may present novel therapeutic strategies.
    Keywords:  Cancer Biology*; Cancer therapeutics; Cell biology*; Drug targets*; Membranes*; Mouse models; SILAC
    DOI:  https://doi.org/10.1074/mcp.RA119.001785
  7. PLoS Biol. 2019 Dec 04. 17(12): e3000535
    Hipolito VEB, Diaz JA, Tandoc KV, Oertlin C, Ristau J, Chauhan N, Saric A, Mclaughlan S, Larsson O, Topisirovic I, Botelho RJ.
      The mechanisms that govern organelle adaptation and remodelling remain poorly defined. The endo-lysosomal system degrades cargo from various routes, including endocytosis, phagocytosis, and autophagy. For phagocytes, endosomes and lysosomes (endo-lysosomes) are kingpin organelles because they are essential to kill pathogens and process and present antigens. During phagocyte activation, endo-lysosomes undergo a morphological transformation, going from a collection of dozens of globular structures to a tubular network in a process that requires the phosphatidylinositol-3-kinase-AKT-mechanistic target of rapamycin (mTOR) signalling pathway. Here, we show that the endo-lysosomal system undergoes an expansion in volume and holding capacity during phagocyte activation within 2 h of lipopolysaccharides (LPS) stimulation. Endo-lysosomal expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly largely independent of the transcription factor EB (TFEB) and transcription factor E3 (TFE3), which are known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTOR Complex 1 (mTORC1)-dependent increase in translation, which appears to be mediated by both S6Ks and 4E-BPs. Moreover, we show that stimulation of RAW 264.7 macrophage cell line with LPS alters translation of a subset but not all of mRNAs encoding endo-lysosomal proteins, thereby suggesting that endo-lysosome expansion is accompanied by functional remodelling. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for endo-lysosome expansion that relies on mTORC1-dependent translation to stimulate endo-lysosome biogenesis in response to an infection signal.
    DOI:  https://doi.org/10.1371/journal.pbio.3000535
  8. Sci Rep. 2019 Dec 04. 9(1): 18329
    Ishimaru K, Yoshioka K, Kano K, Kurano M, Saigusa D, Aoki J, Yatomi Y, Takuwa N, Okamoto Y, Proia RL, Takuwa Y.
      Atherosclerosis is the major cause of ischemic coronary heart diseases and characterized by the infiltration of cholesterol-accumulating macrophages in the vascular wall. Although sphingolipids are implicated in atherosclerosis as both membrane components and lipid mediators, the precise role of sphingolipids in atherosclerosis remains elusive. Here, we found that genetic deficiency of sphingosine kinase-2 (SphK2) but not SphK1 aggravates the formation of atherosclerotic lesions in mice with ApoE deficiency. Bone marrow chimaera experiments show the involvement of SphK2 expressed in bone marrow-derived cells. In macrophages, deficiency of SphK2, a major SphK isoform in this cell type, results in increases in cellular sphingosine and ceramides. SphK2-deficient macrophages have increases in lipid droplet-containing autophagosomes and autolysosomes and defective lysosomal degradation of lipid droplets via autophagy with an impaired luminal acidic environment and proteolytic activity in the lysosomes. Transgenic overexpression of SphK1 in SphK2-deficient mice rescued aggravation of atherosclerosis and abnormalities of autophagosomes and lysosomes in macrophages with reductions of sphingosine, suggesting at least partial overlapping actions of two SphKs. Taken together, these results indicate that SphK2 is required for autophagosome- and lysosome-mediated catabolism of intracellular lipid droplets to impede the development of atherosclerosis; therefore, SphK2 may be a novel target for treating atherosclerosis.
    DOI:  https://doi.org/10.1038/s41598-019-54877-6
  9. Nature. 2019 Dec 04.
    Bazopoulou D, Knoefler D, Zheng Y, Ulrich K, Oleson BJ, Xie L, Kim M, Kaufmann A, Lee YT, Dou Y, Chen Y, Quan S, Jakob U.
      A central aspect of aging research concerns the question of when individuality in lifespan arises1. Here we show that a transient increase in reactive oxygen species (ROS), which occurs naturally during early development in a subpopulation of synchronized Caenorhabditis elegans, sets processes in motion that increase stress resistance, improve redox homeostasis and ultimately prolong lifespan in those animals. We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels. Studies in HeLa cells confirmed that global H3K4me3 levels are ROS-sensitive and that depletion of H3K4me3 levels increases stress resistance in mammalian cell cultures. In vitro studies identified SET1/MLL histone methyltransferases as redox sensitive units of the H3K4-trimethylating complex of proteins (COMPASS). Our findings implicate a link between early-life events, ROS-sensitive epigenetic marks, stress resistance and lifespan.
    DOI:  https://doi.org/10.1038/s41586-019-1814-y
  10. Trends Mol Med. 2019 Nov 29. pii: S1471-4914(19)30286-2. [Epub ahead of print]
    Deus CM, Yambire KF, Oliveira PJ, Raimundo N.
      Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major contributors of chemical energy and building blocks. It is therefore pivotal for cellular function to coordinate the metabolic roles of mitochondria and lysosomes. However, these organelles do more than metabolism, given their function as fundamental signaling platforms in the cell that regulate many key processes such as autophagy, proliferation, and cell death. Mechanisms of crosstalk between mitochondria and lysosomes are discussed, both under physiological conditions and in diseases that affect these organelles.
    Keywords:  autophagy; crosstalk; lysosomes; mitochondria; organelle; signaling
    DOI:  https://doi.org/10.1016/j.molmed.2019.10.009
  11. Elife. 2019 Dec 04. pii: e49930. [Epub ahead of print]8
    Nehammer C, Ejlerskov P, Gopal S, Handley A, Ng L, Moreira P, Lee H, Issazadeh-Navikas S, Rubinsztein DC, Pocock R.
      Appropriate regulation of autophagy is crucial for clearing toxic proteins from cells. Defective autophagy results in accumulation of toxic protein aggregates that detrimentally affect cellular function and organismal survival. Here, we report that the microRNA miR-1 regulates the autophagy pathway through conserved targeting of the orthologous Tre-2/Bub2/CDC16 (TBC) Rab GTPase-activating proteins TBC-7 and TBC1D15 in Caenorhabditis elegans and mammalian cells, respectively. Loss of miR-1 causes TBC-7/TBC1D15 overexpression, leading to a block on autophagy. Further, we found that the cytokine interferon-b (IFN-b) can induce miR-1 expression in mammalian cells, reducing TBC1D15 levels, and safeguarding against proteotoxic challenges. Therefore, this work provides a potential therapeutic strategy for protein aggregation disorders.
    Keywords:  C. elegans; biochemistry; chemical biology; genetics; genomics
    DOI:  https://doi.org/10.7554/eLife.49930
  12. EMBO Rep. 2019 Dec 02. e48469
    Poncet N, Halley PA, Lipina C, Gierliński M, Dady A, Singer GA, Febrer M, Shi YB, Yamaguchi TP, Taylor PM, Storey KG.
      Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. Here, we show that the amino acid transporter Slc7a5/Lat1 is highly expressed in tissues undergoing morphogenesis and that Slc7a5-null mouse embryos have profound neural and limb bud outgrowth defects. Slc7a5-null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylation and apoptosis analyses further indicated induction of the integrated stress response as a potential cause of observed defects. The pattern of stress response gene expression induced in Slc7a5-null embryos was also detected at low level in wild-type embryos and identified stress vulnerability specifically in tissues undergoing morphogenesis. The Slc7a5-null phenotype is reminiscent of Wnt pathway mutants, and we show that Wnt/β-catenin loss inhibits Slc7a5 expression and induces this stress response. Wnt signalling therefore normally supports the metabolic demands of morphogenesis and constrains cellular stress. Moreover, operation in the embryo of the integrated stress response, which is triggered by pathogen-mediated as well as metabolic stress, may provide a mechanistic explanation for a range of developmental defects.
    Keywords:  Slc7a5/Lat1; Wnt signalling; amino acid transport; integrated stress response; mouse embryo morphogenesis
    DOI:  https://doi.org/10.15252/embr.201948469
  13. Biomed Pharmacother. 2019 Nov 28. pii: S0753-3322(19)35313-2. [Epub ahead of print]122 109691
    Wang JL, Xu CJ.
      Astrocytes can serve multiple functions in maintaining cellular homeostasis of the central nervous system (CNS), and normal functions for autophagy in astrocytes is considered to have very vital roles in the pathogenesis of aging and neurodegenerative diseases. Autophagy is a major intracellular lysosomal (or its yeast analog, vacuolar) clearance pathways involved in the degradation and recycling of long-lived proteins, oxidatively damaged proteins and dysfunctional organelles by lysosomes. Current evidence has shown that autophagy might influence inflammation, oxidative stress, aging and function of astrocytes. Although the interrelation between autophagy and inflammation, oxidative stress, aging or neurological disorders have been addressed in detail, the influence of astrocytes mediated-autophagy in aging and neurodegenerative disorders has yet to be fully reviewed. In this review, we will summarize the most up-to-date findings and highlight the role of autophagy in astrocytes and link autophagy of astrocytes to aging and neurodegenerative diseases. Due to the prominent roles of astrocytic autophagy in age-related neurodegenerative diseases, we believe that we can provide new suggestions for the treatment of these disorders.
    Keywords:  Aging; Astrocytes; Autophagy; Mitophagy; Neurodegenerative diseases; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2019.109691
  14. Neurotherapeutics. 2019 Dec 02.
    Naphade S, Tshilenge KT, Ellerby LM.
      Polyglutamine expansion disorders, which include Huntington's disease, have expanded CAG repeats that result in polyglutamine expansions in affected proteins. How this specific feature leads to distinct neuropathies in 11 different diseases is a fascinating area of investigation. Most proteins affected by polyglutamine expansions are ubiquitously expressed, yet their mechanisms of selective neurotoxicity are unknown. Induced pluripotent stem cells have emerged as a valuable tool to model diseases, understand molecular mechanisms, and generate relevant human neural and glia subtypes, cocultures, and organoids. Ideally, this tool will generate specific neuronal populations that faithfully recapitulate specific polyglutamine expansion disorder phenotypes and mimic the selective vulnerability of a given disease. Here, we review how induced pluripotent technology is used to understand the effects of the disease-causing polyglutamine protein on cell function, identify new therapeutic targets, and determine how polyglutamine expansion affects human neurodevelopment and disease. We will discuss ongoing challenges and limitations in our use of induced pluripotent stem cells to model polyglutamine expansion diseases.
    Keywords:  Huntington’s disease; Triplet repeat disorders; induced pluripotent stem cells.; neurodegeneration; polyglutamine
    DOI:  https://doi.org/10.1007/s13311-019-00810-8
  15. Cell Rep. 2019 Dec 03. pii: S2211-1247(19)31463-9. [Epub ahead of print]29(10): 3280-3292.e7
    Wall CE, Rose CM, Adrian M, Zeng YJ, Kirkpatrick DS, Bingol B.
      Dysregulation of mitophagy, whereby damaged mitochondria are labeled for degradation by the mitochondrial kinase PINK1 and E3 ubiquitin ligase Parkin with phosphorylated ubiquitin chains (p-S65 ubiquitin), may contribute to neurodegeneration in Parkinson's disease. Here, we identify a phosphatase antagonistic to PINK1, protein phosphatase with EF-hand domain 2 (PPEF2), that can dephosphorylate ubiquitin and suppress PINK1-dependent mitophagy. Knockdown of PPEF2 amplifies the accumulation of p-S65 ubiquitin in cells and enhances baseline mitophagy in dissociated cortical cultures. Overexpressing enzymatically active PPEF2 reduces the p-S65 ubiquitin signal in cells, and partially purified PPEF2 can dephosphorylate recombinant p-S65 ubiquitin chains in vitro. Using a mass spectrometry approach, we have identified several p-S65-ubiquitinated proteins following mitochondrial damage that are inversely regulated by PPEF2 and PINK1. Interestingly, many of these proteins are involved in nuclear processes such as DNA repair. Collectively, PPEF2 functions to suppress mitochondrial quality control on a cellular level through dephosphorylation of p-S65 ubiquitin.
    Keywords:  PINK1; PPEF2; Parkin; Parkinson’s disease; mitochondria; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2019.10.130
  16. Front Neurol. 2019 ;10 1168
    Torres S, García-Ruiz CM, Fernandez-Checa JC.
      Mitochondrial dysfunction has been recognized as a key player in neurodegenerative diseases, including Alzheimer's disease (AD) and Niemann-Pick type C (NPC) disease. While the pathogenesis of both diseases is different, disruption of intracellular cholesterol trafficking has emerged as a common feature of both AD and NPC disease. Nutritional or genetic mitochondrial cholesterol accumulation sensitizes neurons to Aβ-mediated neurotoxicity in vitro and promotes cognitive decline in AD models. In addition to the primary accumulation of cholesterol and sphingolipids in lysosomes, NPC disease is also characterized by an increase in mitochondrial cholesterol levels in affected organs, predominantly in brain and liver. In both diseases, mitochondrial cholesterol accumulation disrupts membrane physical properties and restricts the transport of glutathione into mitochondrial matrix, thus impairing the mitochondrial antioxidant defense strategy. The underlying mechanisms leading to mitochondrial cholesterol accumulation in AD and NPC diseases are not fully understood. In the present manuscript, we discuss evidence for the potential role of StARD1 in promoting the trafficking of cholesterol to mitochondria in AD and NPC, whose upregulation involves an endoplasmic reticulum stress and a decrease in acid ceramidase expression, respectively. These findings imply that targeting StARD1 or boosting the mitochondrial antioxidant defense may emerge as a promising approach for both AD and NPC disease.
    Keywords:  acid ceramidase; cholesterol; lysosomal disorders; mitochondria; sphingolipids
    DOI:  https://doi.org/10.3389/fneur.2019.01168
  17. Biogerontology. 2019 Dec 04.
    Whitehall JC, Greaves LC.
      Alterations in mitochondrial metabolism have been described as one of the major hallmarks of both ageing cells and cancer. Age is the biggest risk factor for the development of a significant number of cancer types and this therefore raises the question of whether there is a link between age-related mitochondrial dysfunction and the advantageous changes in mitochondrial metabolism prevalent in cancer cells. A common underlying feature of both ageing and cancer cells is the presence of somatic mutations of the mitochondrial genome (mtDNA) which we postulate may drive compensatory alterations in mitochondrial metabolism that are advantageous for tumour growth. In this review, we discuss basic mitochondrial functions, mechanisms of mtDNA mutagenesis and their metabolic consequences, and review the evidence for and against a role for mtDNA mutations in cancer development.
    Keywords:  Ageing; Cancer; Metabolism; Mitochondria; mtDNA mutations
    DOI:  https://doi.org/10.1007/s10522-019-09853-y
  18. Mol Cell. 2019 Nov 25. pii: S1097-2765(19)30813-5. [Epub ahead of print]
    Miao G, Zhang Y, Chen D, Zhang H.
      TMEM39A, encoding an ER-localized transmembrane protein, is a susceptibility locus for multiple autoimmune diseases. The molecular function of TMEM39A remains completely unknown. Here we demonstrated that TMEM39A, also called SUSR2, modulates autophagy activity by regulating the spatial distribution and levels of PtdIns(4)P. Depletion of SUSR2 elevates late endosomal/lysosomal PtdIns(4)P levels, facilitating recruitment of the HOPS complex to promote assembly of the SNARE complex for autophagosome maturation. SUSR2 knockdown also increases the degradative capability of lysosomes. Mechanistically, SUSR2 interacts with the ER-localized PtdIns(4)P phosphatase SAC1 and also the COPII SEC23/SEC24 subunits to promote the ER-to-Golgi transport of SAC1. Retention of SAC1 on the ER in SUSR2 knockdown cells increases the level of PtdIns(3)P produced by the VPS34 complex, promoting autophagosome formation. Our study reveals that TMEM39A/SUSR2 acts as an adaptor protein for efficient export of SAC1 from the ER and provides insights into the pathogenesis of diseases associated with TMEM39A mutations.
    Keywords:  HOPS; PtdIns(4)P; SAC1; SUSR2; TMEM39A; autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2019.10.035
  19. Nat Cell Biol. 2019 Dec;21(12): 1604-1614
    Zhu L, Li Y, Xie X, Zhou X, Gu M, Jie Z, Ko CJ, Gao T, Hernandez BE, Cheng X, Sun SC.
      TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor-TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1-TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1-TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression.
    DOI:  https://doi.org/10.1038/s41556-019-0429-8
  20. Traffic. 2019 Nov 05.
    de Araujo MEG, Liebscher G, Hess MW, Huber LA.
      Lysosomes are key cellular catabolic centers that also perform fundamental metabolic, signaling and quality control functions. Lysosomes are not static and they respond dynamically to intra- and extracellular stimuli triggering changes in organelle numbers, size and position. Such physical changes have a strong impact on lysosomal activity ultimately influencing cellular homeostasis. In this review, we summarize the current knowledge on lysosomal size regulation, on its physiological role(s) and association to several disease conditions.
    Keywords:  AMPK; BORC; LAMTOR; PIKfyve; PtdIns(3)P; PtdIns(3,5)P2; PtdIns(4,5)P2; V-ATPase; autolysosome; autophagy; endolysosome; fission; fusion; late endosome; lysosomal acidification; lysosomal reformation; lysosomal storage disorders; lysosome
    DOI:  https://doi.org/10.1111/tra.12714