bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2019‒03‒17
seventeen papers selected by
Viktor Korolchuk
Newcastle University

  1. Autophagy. 2019 Mar 14. 1-19
      Autophagosome-lysosome fusion is a common critical step in various forms of macroautophagy including mitophagy, the selective degradation of mitochondria. Regulations of this fusion process remain poorly defined. Here we have determined the role of the sigma-1 receptor (Sig1R), a unique endoplasmic reticulum membrane protein. Knockout of Sig1R impaired mitochondrial clearance without altering the PINK1/Parkin signaling, in mouse retinal explants and cultured cells treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) for induction of mitophagy. Sig1R depletion also caused accumulation of autophagosome markers LC3-II and SQSTM1, but did not change the levels of Beclin1 and ATG7, proteins associated with autophagosome biogenesis. Lysosomal pH and protease activities were not negatively affected. However, Sig1R knockout partially compromised autophagosome-lysosome fusion in CCCP-treated NSC34 cells, as revealed by reduced GFP fluorescence quenching of GFP-RFP-LC3-II puncta and co-localization of lysosomes with mitochondria. Furthermore, Sig1R co-immunoprecipitated with ATG14, STX17, and VAMP8 (but not SNAP29), proteins key to autophagosome-lysosome membrane fusion. Re-expressing Sig1R in the null background rescued clearance of mitochondria and autophagosomes. In summary, we started out finding that Sig1R knockout impaired the clearance of mitochondria and autophagosomes, and then narrowed down the Sig1R modulation to the autophagosome-lysosome fusion step. This study may shed new light on understanding autophagy-associated cyto-protection and disease mechanisms. Abbreviations: APEX2, a genetically engineered peroxidase; BiFC, bimolecule fluorescence complementation; CCCP, a mitophagy inducing compound; CRISPR, clustered regularly interspaced short palindromic repeats; EM, electron microscopy; ER, endoplasmic reticulum; LC3, Microtubule-associated protein 1A/1B-light chain 3; Sig1R, sigma-1 receptor.
    Keywords:  CRISPR knockout and knockdown; Sigma-1 receptor; autophagosome-lysosome fusion; autophagy; mitophagy
  2. Sci Rep. 2019 Mar 11. 9(1): 4107
      The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.
  3. Autophagy. 2019 Mar 12.
      Macroautophagy/autophagy is a degradative process essential for various cellular processes. We previously demonstrated that autophagy-deficiency causes myoblast apoptosis and impairs myotube formation. In this study, we continued this work with particular emphasis on mitochondrial remodelling and stress/apoptotic signaling. We found increased (p<0.05) autophagic (e.g., altered LC3B levels, increased ATG7, decreased SQSTM1) and mitophagic (e.g., BNIP3 upregulation, mitochondrial localized GFP-LC3 puncta, and elevated mitochondrial LC3B-II) signaling during myoblast differentiation. shRNA-mediated knockdown of ATG7 (shAtg7) decreased these autophagic and mitophagic responses, while increasing CASP3 activity and ANXA5/annexin V staining in differentiating myoblasts; ultimately resulting in dramatically impaired myogenesis. Further confirming the importance of mitophagy in these responses, CRISPR-Cas9-mediated knockout of Bnip3 (bnip3-/-) resulted in increased CASP3 activity and DNA fragmentation as well as impaired myoblast differentiation. In addition, shAtg7 myoblasts displayed greater endoplasmic reticulum (e.g., increased CAPN activity and HSPA) and mitochondrial (e.g., mPTP formation, reduced mitochondrial membrane potential, elevated mitochondrial 4-HNE) stress. shAtg7 and bnip3-/- myoblasts also displayed altered mitochondria-associated signaling (e.g., PPARGC1A, DNM1L, OPA1) and protein content (e.g., SLC25A4, VDAC1, CYCS). Moreover, shAtg7 myoblasts displayed CYCS and AIFM1 release from mitochondria, and CASP9 activation. Similarly, bnip3-/- myoblasts had significantly higher CASP9 activation during differentiation. Importantly, administration of a chemical inhibitor of CASP9 (Ac-LEHD-CHO) or dominant-negative CASP9 (ad-DNCASP9) partially recovered differentiation and myogenesis in shAtg7 myoblasts. Together, these data demonstrate an essential role for autophagy in protecting myoblasts from mitochondrial oxidative stress and apoptotic signaling during differentiation, as well as in the regulation of mitochondrial network remodelling and myogenesis.
    Keywords:  apoptosis; autophagy; caspase 9; differentiation; mitochondria; mitophagy; myogenesis; oxidative stress; skeletal muscle
  4. Cells. 2019 Mar 12. pii: E236. [Epub ahead of print]8(3):
      During macroautophagy, the human WIPI (WD-repeat protein interacting with phosphoinositides) proteins (WIPI1⁻4) function as phosphatidylinositol 3-phosphate effectors at the nascent autophagosome. Likewise, the two WIPI homologues in Caenorhabditis elegans, ATG-18 and EPG-6, play important roles in autophagy, whereby ATG-18 is considered to act upstream of EPG-6 at the onset of autophagy. Due to its essential role in autophagy, ATG-18 was found to be also essential for lifespan extension in Caenorhabditis elegans; however, this has not yet been addressed with regard to EPG-6. Here, we wished to address this point and generated mutant strains that expressed the autophagy marker GFP::LGG-1 (GFP-LC3 in mammals) and harbored functional deletions of either atg-18 (atg18(gk378)), epg-6 (epg-6(bp242)) or both (atg-18(gk378);epg-6(bp242)). Using quantitative fluorescence microscopy, Western blotting, and lifespan assessments, we provide evidence that in the absence of either ATG-18 or EPG-6 autophagy was impaired, and while atg-18 mutant animals showed a short-lived phenotype, lifespan was significantly increased in epg-6 mutant animals. We speculate that the long-lived phenotype of epg-6 mutant animals points towards an autophagy-independent function of EPG-6 in lifespan control that warrants further mechanistic investigations in future studies.
    Keywords:  ATG-18; EPG-6; GFP::LGG-1; WIPI3; WIPI4; autophagy; lifespan
  5. Contact (Thousand Oaks). 2018 Jan-Dec;2:2
      Peroxisomes play important roles in lipid metabolism. Surplus or damaged peroxisomes can be selectively targeted for autophagic degradation, a process termed pexophagy. Maintaining a proper level of pexophagy is critical for cellular homeostasis. Here we found that endoplasmic reticulum (ER)-mitochondria contact sites are necessary for efficient pexophagy. During pexophagy, the peroxisomes destined for degradation are adjacent to the ER-mitochondria encounter structure (ERMES) that mediates formation of ER- mitochondria contacts; disruption of the ERMES results in a severe defect in pexophagy. We show that a mutant form of Mdm34, a component of the ERMES, which impairs ERMES formation and diminishes its association with the peroxisomal membrane protein Pex11, also leads to defects in pexophagy. The dynamin-related GTPase Vps1, which is specific for peroxisomal fission, is recruited to the peroxisomes at ER-mitochondria contacts by the selective autophagy scaffold Atg11 and the pexophagy receptor Atg36, facilitating peroxisome degradation.
    Keywords:  ER-mitochondria contact sites; peroxisomes; pexophagy; stress; yeast
  6. Cells. 2019 Mar 08. pii: E224. [Epub ahead of print]8(3):
      The small GTPase, Rab7a, and the regulators of its GDP/GTP-binding status were shown to have roles in both endocytic membrane traffic and autophagy. Classically known to regulate endosomal retrograde transport and late endosome-lysosome fusion, earlier work has indicated a role for Rab7a in autophagosome-lysosome fusion as well as autolysosome maturation. However, as suggested by recent findings on PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy, Rab7a and its regulators are critical for the correct targeting of Atg9a-bearing vesicles to effect autophagosome formation around damaged mitochondria. This mitophagosome formation role for Rab7a is dependent on an intact Rab cycling process mediated by the Rab7a-specific guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs). Rab7a activity in this regard is also dependent on the retromer complex, as well as phosphorylation by the TRAF family-associated NF-κB activator binding kinase 1 (TBK1). Here, we discuss these recent findings and broadened perspectives on the role of the Rab7a network in PINK1-Parkin mediated mitophagy.
    Keywords:  Rab7; TBC1D15/17; TRAF family-associated NF-κB activator binding kinase 1 (TBK1); Tre-2/Bub2/Cdc16 (TBC)1D5; autophagy; mitophagosome; mitophagy
  7. J Biol Chem. 2019 Mar 11. pii: jbc.RA118.006595. [Epub ahead of print]
      Mitochondria are major sites of energy metabolism that influence numerous cellular events including immunity and cancer development. Previously, we reported that the mitochondrion specific antioxidant enzyme, manganese containing superoxide dismutase (MnSOD), has dual roles in early- and late- carcinogenesis stages. However, how defective MnSOD impacts the chain of events that leads to cell transformation in pathologically normal epidermal cells that have been exposed to carcinogens is unknown. Here, we show that UVB radiation causes nitration and inactivation of MnSOD leading to mitochondrial injury and mitophagy. In keratinocytes, exposure to UVB radiation decreased mitochondrial oxidative phosphorylation, increased glycolysis and the expression of autophagy-related genes, and enhanced AKT Ser/Thr kinase (AKT) phosphorylation and cell growth. Interestingly, UVB initiated a prosurvival mitophagy response by mitochondria-mediated reactive oxygen species (ROS) signaling via the mammalian target of the mTOR complex 2 (mTORC2) pathway.  Knock-down of rictor but not raptor abrogated UVB-induced mitophagy responses. Furthermore, fractionation and proximity-ligation assays reveal that ROS-mediated mTOC2 activation in mitochondria is necessary for UVB-induced mitophagy. Importantly, pretreatment with the MnSOD mimic MnTnBuOE-2-PyP5+ (MnP) attenuates mTORC2 activation and suppresses UVB-induced mitophagy. UVB radiation exposure also increased cell growth as assessed by soft-agar colony survival and cell growth assays, and pretreatment with MnP or the known autophagy inhibitor 3-MA, abrogated UVB-induced cell growth. These results indicat that MnSOD is a major redox regulator that maintains mitochondrial health and show that UVB-mediated MnSOD inactivation promotes mitophagy and thereby prevents accumulation of damaged mitochondria.
    Keywords:  MnSOD; autophagy; cancer; mTOR; mTOR complex 2 (mTOR C2); metabolism; mitophagy; oxidative stress; reactive oxygen species (ROS); rictor
  8. Autophagy. 2019 Mar 13.
      The destruction of mitochondria through macroautophagy/autophagy has been recognized as a major route of mitochondrial protein degradation since its discovery more than fifty years ago, but fundamental questions remain unanswered. First, how much mitochondrial protein turnover occurs through autophagy? Mitochondrial proteins are also degraded by nonautophagic mechanisms, and the proportion of mitochondrial protein turnover that occurs through autophagy is still unknown. Second, does autophagy degrade mitochondrial proteins uniformly or selectively? Autophagy was originally thought to degrade all mitochondrial proteins at the same rate, but recent work suggests that mitochondrial autophagy may be protein selective. To investigate these questions, we used a proteomics-based approach in the fruit fly Drosophila melanogaster, comparing mitochondrial protein turnover rates in autophagy-deficient Atg7 mutants and controls. We found that ~35% of mitochondrial protein turnover occurred via autophagy. Similar analyses using park/parkin mutants revealed that park-dependent mitophagy accounted for ~25% of mitochondrial protein turnover, suggesting that most mitochondrial autophagy specifically eliminates dysfunctional mitochondria. We also found that our results were incompatible with uniform autophagic turnover of mitochondrial proteins and consistent with protein-selective autophagy. In particular, the autophagic turnover rates of individual mitochondrial proteins varied widely, and only a small amount of the variation could be attributed to tissue differences in mitochondrial composition and autophagy rate. Furthermore, analyses comparing autophagy-deficient and control human fibroblasts revealed diverse autophagy-dependent turnover rates even in homogeneous cells. In summary, our work indicates that autophagy acts selectively on mitochondrial proteins, and that most mitochondrial protein turnover occurs through nonautophagic processes.
    Keywords:  ; autophagy; mitochondria; mitophagy; protein degradation; protein turnover; proteomics; stable isotope labeling; turnover rate
  9. Mol Cell. 2019 Feb 28. pii: S1097-2765(19)30061-9. [Epub ahead of print]
      Xenophagy, a selective autophagy pathway that protects the cytosol against bacterial invasion, relies on cargo receptors that juxtapose bacteria and phagophore membranes. Whether phagophores are recruited from a constitutive pool or are generated de novo at prospective cargo remains unknown. Phagophore formation in situ would require recruitment of the upstream autophagy machinery to prospective cargo. Here, we show that, essential for anti-bacterial autophagy, the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, which are subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively. FIP200 and SINTBAD/NAP1 are each recruited independently to bacteria via NDP52, as revealed by selective point mutations in their respective binding sites, but only in their combined presence does xenophagy proceed. Such recruitment of the upstream autophagy machinery by NDP52 reveals how detection of cargo-associated "eat me" signals, induction of autophagy, and juxtaposition of cargo and phagophores are integrated in higher eukaryotes.
    Keywords:  FIP200; NDP52; Salmonella enterica; TBK1; ULK; cargo receptor; galectin-8; selective autophagy; xenophagy
  10. J Biol Chem. 2019 Mar 15. pii: jbc.RA118.006763. [Epub ahead of print]
      The E3 ubiquitin ligase parkin is a critical regulator of mitophagy and has been identified as a susceptibility gene for type 2 diabetes (T2D). However, its role in metabolically active tissues that precipitate T2D development is unknown. Specifically, pancreatic β cells and adipocytes both rely heavily on mitochondrial function in the regulation of optimal glycemic control to prevent T2D, but parkin's role in preserving quality control of β-cell or adipocyte mitochondria is unclear. Although parkin has been previously reported to control mitophagy, here we show that parkin surprisingly is dispensable for glucose homeostasis in both β cells and adipocytes during diet-induced insulin resistance in mice. We observed that insulin secretion, β-cell formation, and islet architecture were preserved in parkin-deficient β cells and islets, suggesting that parkin is not necessary for control of β-cell function and islet compensation for diet-induced obesity. Although transient parkin deficiency mildly impaired mitochondrial turnover in β-cell lines, parkin deletion in primary β cells yielded no deficits in mitochondrial clearance. In adipocyte-specific deletion models, lipid uptake and β-oxidation were increased in cultured cells, whereas adipose tissue morphology, glucose homeostasis, and the beige-to-white adipocyte transition were unaffected in vivo. In key metabolic tissues where mitochondrial dysfunction has been implicated in T2D development, our experiments unexpectedly revealed that parkin is not an essential regulator of glucose tolerance, whole-body energy metabolism, or mitochondrial quality control. These findings highlight that parkin-independent processes maintain β-cell and adipocyte mitochondrial quality control in diet-induced obesity.
    Keywords:  E3 ubiquitin ligase; adipocyte; adipose tissue; autophagy; beta cell (B-cell); diabetes; islet; metabolism; mitochondria; mitophagy
  11. Mol Cell. 2019 Mar 06. pii: S1097-2765(19)30100-5. [Epub ahead of print]
      Selective autophagy recycles damaged organelles and clears intracellular pathogens to prevent their aberrant accumulation. How ULK1 kinase is targeted and activated during selective autophagic events remains to be elucidated. In this study, we used chemically inducible dimerization (CID) assays in tandem with CRISPR KO lines to systematically analyze the molecular basis of selective autophagosome biogenesis. We demonstrate that ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex. The capability of NDP52 to induce mitophagy is dependent on its interaction with the FIP200/ULK1 complex, which is facilitated by TBK1. Ectopically tethering ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. Focal activation of ULK1 occurs independently of AMPK and mTOR. Our findings provide a parsimonious model of selective autophagy, which highlights the coordination of ULK1 complex localization by autophagy receptors and TBK1 as principal drivers of targeted autophagosome biogenesis.
    Keywords:  ATG13; FIP200; P62; PINK1; Parkin; TAX1BP1; lysosome; mitochondria; mitophagy; optineurin
  12. Front Mol Neurosci. 2019 ;12 46
      Regulated cell death (RCD) plays a fundamental role in human health and disease. Apoptosis is the best-studied mode of RCD, but the importance of other modes has recently been gaining attention. We have previously demonstrated that adult rat hippocampal neural stem (HCN) cells undergo autophagy-dependent cell death (ADCD) following insulin withdrawal. Here, we show that Parkin mediates mitophagy and ADCD in insulin-deprived HCN cells. Insulin withdrawal increased the amount of depolarized mitochondria and their colocalization with autophagosomes. Insulin withdrawal also upregulated both mRNA and protein levels of Parkin, gene knockout of which prevented mitophagy and ADCD. c-Jun is a transcriptional repressor of Parkin and is degraded by the proteasome following insulin withdrawal. In insulin-deprived HCN cells, Parkin is required for Ca2+ accumulation and depolarization of mitochondria at the early stages of mitophagy as well as for recognition and removal of depolarized mitochondria at later stages. In contrast to the pro-death role of Parkin during mitophagy, Parkin deletion rendered HCN cells susceptible to apoptosis, revealing distinct roles of Parkin depending on different modes of RCD. Taken together, these results indicate that Parkin is required for the induction of ADCD accompanying mitochondrial dysfunction in HCN cells following insulin withdrawal. Since impaired insulin signaling is implicated in hippocampal deficits in various neurodegenerative diseases and psychological disorders, these findings may help to understand the mechanisms underlying death of neural stem cells and develop novel therapeutic strategies aiming to improve neurogenesis and survival of neural stem cells.
    Keywords:  Parkin; autophagy-dependent cell death; c-Jun; hippocampal neural stem cells; mitophagy
  13. Cell Rep. 2019 Mar 12. pii: S2211-1247(19)30231-1. [Epub ahead of print]26(11): 3037-3050.e4
      FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation. Furthermore, SHOC2 selectively binds to Raptor to competitively inhibit the Raptor-mTOR binding to inactivate mTORC1 and induce autophagy, whereas Raptor binding of SHOC2 inhibits the SHOC2-RAS binding to block the MAPK pathway and proliferation. Finally, SHOC2 is overexpressed in pancreatic cancer, which correlated with poor patient survival. SHOC2 mutations were found in lung cancer tissues with gain-of-function activity. Collectively, the SHOC2-Raptor interaction triggers negative cross-talk between RAS-ERK and mTORC1 pathways, whereas FBXW7 regulates both pathways by targeting SHOC2 for ubiquitylation and degradation.
    Keywords:  FBXW7; MAPK; RAS-RAF-ERK; Raptor; SCF E3 ligase; SHOC2; autophagy; cell proliferation; mTOR; ubiquitylation and degradation
  14. Cell Rep. 2019 Mar 12. pii: S2211-1247(19)30208-6. [Epub ahead of print]26(11): 3051-3060.e4
      Cancer cells heavily depend on the amino acid glutamine to meet the demands associated with growth and proliferation. Due to the rapid consumption of glutamine, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation by using RNA-seq analysis. We show that Slc7a3, an arginine transporter, is significantly induced by p53. We also show that increased intracellular arginine levels following glutamine deprivation are dependent on p53. The influx of arginine has minimal effects on known metabolic pathways upon glutamine deprivation. Instead, we found arginine serves as an effector for mTORC1 activation to promote cell growth in response to glutamine starvation. Therefore, we identify a p53-inducible gene that contributes to the metabolic stress response.
    Keywords:  Slc7a3; arginine; glutamine deprivation; p53 activation
  15. EMBO Rep. 2019 Mar 13. pii: e46832. [Epub ahead of print]
      Parkin is an ubiquitin-E3 ligase that acts as a key component of the cellular machinery for mitophagy. We show here that Parkin expression is reciprocally regulated in brown adipose tissue in relation to thermogenic activity. Thermogenic stimuli repress Parkin gene expression via transcriptional mechanisms that are elicited by noradrenergic and PPARα-mediated pathways that involve intracellular lipolysis in brown adipocytes. Parkin-KO mice show over-activated brown adipose tissue thermogenic activity and exhibit improved metabolic parameters, especially when fed a high-fat diet. Deacclimation, which is the return of a cold-adapted mouse to a thermoneutral temperature, dramatically induces mitophagy in brown adipocytes, with a concomitant induction of Parkin levels. We further reveal that Parkin-KO mice exhibit defects in the degradative processing of mitochondrial proteins in brown adipose tissue in response to deacclimation. These results suggest that the transcriptional control of Parkin in brown adipose tissue may contribute to modulating the mitochondrial mass and activity for adaptation to thermogenic requirements.
    Keywords:  adiposity; autophagy; mitophagy; obesity
  16. Mol Cell Biochem. 2019 Mar 15.
      Silkworm (Bombyx mori) is not only a model organism for scientific studies, but also a commercial insect for agricultural production. BmAtg8 (a B. mori homolog of yeast Atg8) plays crucial roles in macroautophagy (hereafter referred to autophagy), which is helpful for silkworm metamorphosis. Relevant mechanism about BmAtg8 currently remains ambiguous. Based on our previous acetylome of B. mori after BmNPV infection, we focused on that acetylation of BmAtg8 K13 was changed upon virus challenge. Subsequently, anti-BmAtg8 antibody was generated, and EBSS-induced BmN cellular autophagy model was established. Next, by constructing acetylation-mimic K13Q or deacetylation-mimic K13R mutant BmAtg8, we further examined that K13 of BmAtg8 was acetylated after BmNPV infection and chose 3 h as an appropriate point after EBSS treatment for autophagy initiation. Furthermore, acetylation of BmAtg8 K13 significantly reduced BmAtg8-PE formation in the presence of EBSS, thereby interfering autophagy initiation. Interestingly, acetylated K13 of BmAtg8 contributed to weaken interaction with Atg7, which may influence BmAtg8-PE conjugation. Eventually, acetylation of BmAtg8 K13 is critical for attenuating cell rescue through impaired autophagy initiation. Taken together, our data support an acetylated molecular function for BmAtg8 during starvation-induced autophagy, and provide insights into the modulating mechanisms that potentially reveal the LC3 (a mammalian homolog of Atg8) function in mammal.
    Keywords:  Acetylation; Autophagy; BmAtg8; Cell death; Starvation
  17. Cells. 2019 Mar 14. pii: E241. [Epub ahead of print]8(3):
      Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin⁻proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of safety mechanism. If one of these degradation systems is hampered, the other compensates for this defect. The mechanism behind this crosstalk is poorly understood. Novel studies suggest that primary cilia, little cellular protrusions, are involved in the regulation of the crosstalk between the two degradation systems. In this review article, we summarise the current knowledge about the association between cilia, the ubiquitin⁻proteasome system and autophagy.
    Keywords:  BBS4; GLI; IFT; OFD1; RPGRIP1L; hedgehog; mTOR; neurodegenerative diseases; protein aggregation