bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021–05–16
sixteen papers selected by
  1. RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.
  2. TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation.
  3. Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study.
  4. Impact of mTOR signaling pathway on CD8+ T cell immunity through Eomesodermin in response to invasive candidiasis.
  5. ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
  6. TSC loss is a clonal event in eosinophilic solid and cystic renal cell carcinoma: a multiregional tumor sampling study.
  7. Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis.
  8. [Genetic screening and prenatal diagnosis in high-risk families with tuberous sclerosis complex syndrome].
  9. Involvement of mental health professionals in the treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND): results of a multinational European electronic survey.
  10. OCRL regulates lysosome positioning and mTORC1 activity through SSX2IP-mediated microtubule anchoring.
  11. A Hepatocellular Carcinoma Patient with TSC1 Mutations Benefits from Treatment with Everolimus: A Case Report.
  12. Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons.
  13. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways.
  14. V-ATPase controls tumor growth and autophagy in a Drosophila model of gliomagenesis.
  15. mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain.
  16. Did Everolimus Break the Rules?
  1. Nat Commun. 2021 May 10. 12(1): 2589
    RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.
    Timothy S Catlett, Massimo M Onesto, Alec J McCann, Sarah K Rempel, Jennifer Glass, David N Franz, Timothy M Gómez.
      Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.
    DOI:  https://doi.org/10.1038/s41467-021-22770-4
  2. Mol Cell. 2021 Apr 30. pii: S1097-2765(21)00324-5. [Epub ahead of print]
    TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation.
    Katharina Fitzian, Anne Brückner, Laura Brohée, Reinhard Zech, Claudia Antoni, Stephan Kiontke, Raphael Gasper, Anna Livia Linard Matos, Stephanie Beel, Sabine Wilhelm, Volker Gerke, Christian Ungermann, Mark Nellist, Stefan Raunser, Constantinos Demetriades, Andrea Oeckinghaus, Daniel Kümmel.
      The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P2, demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling.
    Keywords:  TSC; X-ray crystallography; lysosomes; mTORC1; membrane binding; phosphatidylinositol phosphate
    DOI:  https://doi.org/10.1016/j.molcel.2021.04.019
  3. Front Med (Lausanne). 2021 ;8 605909
    Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study.
    Silvia Terraneo, Elena Lesma, Silvia Ancona, Gianluca Imeri, Giuseppina Palumbo, Olga Torre, Lisa Giuliani, Stefano Centanni, Angela Peron, Silvia Tresoldi, Paola Cetrangolo, Fabiano Di Marco.
      Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM. Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls. Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively. Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.
    Keywords:  biomarkers; lymphangiomeiomyomatosis; matrix metalloproteinases; tuberous sclerosis complex; vascular endothelial growth factor
    DOI:  https://doi.org/10.3389/fmed.2021.605909
  4. J Microbiol Immunol Infect. 2021 Apr 20. pii: S1684-1182(21)00090-6. [Epub ahead of print]
    Impact of mTOR signaling pathway on CD8+ T cell immunity through Eomesodermin in response to invasive candidiasis.
    Jiahui Zhang, Na Cui, Hao Wang, Wen Han, Guangxu Bai, Wei Cheng.
       BACKGROUND: We investigated the effect of the mammalian target of rapamycin (mTOR) pathway on CD8+ T cell immunity through Eomesodermin (Eomes) in intensive care unit (ICU) patients with invasive candidiasis (IC) and in a mouse model.
    METHODS: We evaluated quantitative changes in parameters of the mTOR/phosphorylated ribosomal S6 kinase (pS6K) pathway and immune system at the onset of infection in ICU patients. The study was registered on 28 February 2017 at chictr.org.cn (ChiCTR-ROC-17010750). We also used a mouse model of Candida infection and constructed T-cell-specific mTOR and T-cell-specific tuberous sclerosis complex (TSC) 1 conditional knockout mice to elucidate the molecular mechanisms.
    RESULTS: We enrolled 88 patients, including 8 with IC. The IC group had lower CD8+ T cell counts, higher serum levels of mTOR, pS6K, Eomes and interleukin (IL)-6. The mouse model with IC showed results consistent in the clinical study. The CD8+ T cell immune response to IC seemed to be weakened in TSC1 knockout mice compared with wild-type IC mice, demonstrating that mTOR activation resulted in the impaired CD8+ T cell immunity in IC.
    CONCLUSIONS: In IC, the mTOR activation may play a vital role in impaired CD8+ T cell immunity through enhancing expression of Eomes. The study was registered on 28 February 2017 at chictr.org.cn (identifier ChiCTR-ROC-17010750).
    Keywords:  CD8+ T cells; Eomesodermin; Invasive candidiasis; Mammalian target of rapamycin
    DOI:  https://doi.org/10.1016/j.jmii.2021.03.021
  5. EMBO J. 2021 May 14. e106412
    ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
    Delong Meng, Qianmei Yang, Chase H Melick, Brenden C Park, Ting-Sung Hsieh, Adna Curukovic, Mi-Hyeon Jeong, Junmei Zhang, Nicholas G James, Jenna L Jewell.
      The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid-deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature-sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.
    Keywords:  ArfGAP1; amino acids; lysosome; mTORC1; vesicle trafficking
    DOI:  https://doi.org/10.15252/embj.2020106412
  6. Mod Pathol. 2021 May 14.
    TSC loss is a clonal event in eosinophilic solid and cystic renal cell carcinoma: a multiregional tumor sampling study.
    Enrico Munari, Giulio Settanni, Anna Caliò, Diego Segala, Sara Lonardi, Silvia Sandrini, Paola Vacca, Nicola Tumino, Marcella Marconi, Matteo Brunelli, Stefano Gobbo, George J Netto, Lorenzo Moretta, Giuseppe Zamboni, Guido Martignoni.
      Eosinophilic, solid and cystic (ESC) renal cell carcinoma (RCC) is characterized by a solid and cystic architecture with cells showing abundant eosinophilic cytoplasm with hobnail arrangement and a cytokeratin 7-negative/cytokeratin 20-positive immunophenotype. Recent studies have suggested that bi-allelic events affecting TSC genes might play an important role for such tumors. However, only indirect evidence of the clonal origin of TSC mutation has been gathered so far. Therefore, in this paper we aimed to perform multi-regional tumor sampling molecular analysis in four ESC RCC cases that had been completely embedded, three sporadic and one occurring in a patient with tuberous sclerosis complex (TSC). Histologically, the 4 cases showed cystic and solid architecture and cells with abundant eosinophilic cytoplasm with cytoplasmic stippling and round to oval nuclei. Immunohistochemistry showed at least focal expression of cytokeratin 20 in all tissue samples and negative cytokeratin 7, as well as diffuse positivity for S100A1 and at least focal expression of cathepsin K in three out of four cases. The sporadic cases showed the same somatic TSC1 mutations in all tissue samples analyzed, while the TSC-associated case showed the same TSC1 alteration in both normal tissue and all tumor samples analyzed, proving the germline nature of the alteration. In conclusion, our data demonstrate that clonal TSC loss is a key event in ESC RCC and support considering ESC RCC as an entity given its distinct morphologic, immunophenotypical and molecular characteristics.
    DOI:  https://doi.org/10.1038/s41379-021-00816-8
  7. Front Immunol. 2021 ;12 638575
    Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis.
    Lanman Xu, Xiaofang Wang, Yan Chen, Lynn Soong, Yongping Chen, Jiyang Cai, Yuejin Liang, Jiaren Sun.
      Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.
    Keywords:  T cell; mTOR; metformin; mitochondria; viral hepatitis
    DOI:  https://doi.org/10.3389/fimmu.2021.638575
  8. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 May 10. 38(5): 435-438
    [Genetic screening and prenatal diagnosis in high-risk families with tuberous sclerosis complex syndrome].
    Rui Lin, Zhenhua Zhao, Li'na Liu, Conghui Wang, Chen Chen, Ning Liu, Jingjing Meng, Xiangdong Kong.
       OBJECTIVE: To carry out genetic testing and prenatal diagnosis for 29 Chinese pedigrees affected with tuberous sclerosis complex (TSC) and assess efficacy of combined next generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA) for the diagnosis.
    METHODS: NGS and MLPA were used in conjunct to detect variants of TSC1 and TSC2 genes among the probands of the pedigrees. Paternity test was carried out to exclude maternal DNA contamination. Prenatal diagnosis was provided to 14 couples based on the discoveries in the probands.
    RESULTS: Twenty-seven variants were identified in the TSC1 and TSC2 genes among the 29 pedigrees, which yielded a detection rate of 93.1%. Respectively, 5 (18.5%) and 22 (81.5%) variants were identified in the TSC1 and TSC2 genes. Twelve variants were unreported previously. Prenatal diagnosis showed that five fetuses were affected with TSC, whilst the remaining nine were unaffected.
    CONCLUSION: Above finding has expanded the spectrum of TSC1 and TSC2 gene variants. Combined NGS and MLPA has enabled diagnosis of TSC with efficiency and accuracy.
    DOI:  https://doi.org/10.3760/cma.j.cn511374-20200325-00203
  9. Orphanet J Rare Dis. 2021 May 12. 16(1): 216
    Involvement of mental health professionals in the treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND): results of a multinational European electronic survey.
    Robert Waltereit, Guillaume Beaure d'Augères, Jasna Jancic, John Chris Kingswood, Maya Koleva, Ruben Marques, Vicente Villanueva, Stéphane Auvin.
       BACKGROUND: Tuberous sclerosis complex (TSC) is a rare, genetic, multisystem disorder characterized by the growth of hamartomas in several organs, including the brain, kidneys, heart, eyes, and lungs. Even though over 90% of patients will have some form of TSC-associated neuropsychiatric disorder (TAND), there is an apparent lack of involvement of mental health professionals (MHPs) in the care of patients with TSC. The aim of this study was to determine the current level of TAND awareness in the TSC community and to identify possible barriers to effective multidisciplinary collaboration between MHPs and other healthcare providers (HCPs) in TAND management.
    METHODS: An electronic survey on current TSC and TAND management was conducted, targeting TSC caregivers/families, psychiatrists, neurologists, TSC specialists, and primary care physicians.
    RESULTS: The invitation to participate in the survey was emailed to 659 HCPs and was disseminated through social media channels of patient advocacy groups. The survey was open for 4 months, with 359 responses collected. The majority of participants were TSC caregivers/families (73.3% of all responses). Of the 96 HCPs who participated, most were neurologists (61.5%) or TSC specialists (28.1%). Only 6 psychiatrists and 4 primary care physicians participated. Approximately half of patients have never had a neuropsychiatric assessment, and it was their caregivers/families who initiated the discussion of TAND with their providers. Almost 70% of TSC caregivers/families believed that psychiatric treatment could improve their quality of life. However, 54% of patients had difficulty obtaining psychiatric assessment. In turn, only 21% of HCPs believed that psychiatric therapy would help and 74% were concerned that their patients would be stigmatized by psychiatric referral.
    CONCLUSIONS: This study focused on European healthcare systems suggests that current care for mental health issues in patients with TSC is inadequate, despite guideline recommendations for regular neuropsychiatric assessments. This appears to be due to a combination of gaps in diagnosis and surveillance, low frequency of psychiatric referrals, insufficient resources, and stigmatization of mental healthcare. There is a pressing need for further initiatives to study and address the mechanisms underlying the mental health treatment gap. The importance of MHP support must be recognized to optimize TSC management.
    Keywords:  TAND; TAND checklist; TSC-associated neuropsychiatric disorders; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1186/s13023-021-01800-w
  10. EMBO Rep. 2021 May 13. e52173
    OCRL regulates lysosome positioning and mTORC1 activity through SSX2IP-mediated microtubule anchoring.
    Biao Wang, Wei He, Philipp P Prosseda, Liang Li, Tia J Kowal, Jorge A Alvarado, Qing Wang, Yang Hu, Yang Sun.
      Lysosomal positioning and mTOR (mammalian target of rapamycin) signaling coordinate cellular responses to nutrient levels. Inadequate nutrient sensing can result in growth delays, a hallmark of Lowe syndrome. OCRL mutations cause Lowe syndrome, but the role of OCRL in nutrient sensing is unknown. Here, we show that OCRL is localized to the centrosome by its ASH domain and that it recruits microtubule-anchoring factor SSX2IP to the centrosome, which is important in the formation of the microtubule-organizing center. Deficiency of OCRL in human and mouse cells results in loss of microtubule-organizing centers and impaired microtubule-based lysosome movement, which in turn leads to mTORC1 inactivation and abnormal nutrient sensing. Centrosome-targeted PACT-SSX2IP can restore microtubule anchoring and mTOR activity. Importantly, boosting the activity of mTORC1 restores the nutrient sensing ability of Lowe patients' cells. Our findings highlight mTORC1 as a novel therapeutic target for Lowe syndrome.
    Keywords:  OCRL; lowe syndrome; lysosome positioning; mTOR; microtubule nucleation
    DOI:  https://doi.org/10.15252/embr.202052173
  11. Visc Med. 2021 Mar;37(2): 116-119
    A Hepatocellular Carcinoma Patient with TSC1 Mutations Benefits from Treatment with Everolimus: A Case Report.
    Hua-Sheng Shi, Shuo Wang, Man-Jiang Li, Li-Qun Wu.
      Hepatocellular carcinoma (HCC) has a high degree of malignancy and poor prognosis. Treatment options for patients with advanced HCC are limited. There is currently no evidence to approve the accumulation of targeted therapies for HCC to support the inhibition of the PI3K/Akt/mTOR signaling pathway as an effective therapeutic strategy. We report on a patient with advanced HCC carrying the TSC1 gene mutation who responded well to the mammalian target of rapamycin inhibitor everolimus. Computed tomography revealed tumor shrinkage and maintenance of partial remission after everolimus treatment for >12.3 months. To the best of our knowledge, this is the first clinical case report showing benefit from everolimus treatment in HCC patients with TSC1 gene mutations. Therefore, everolimus may be used as a potential targeted therapy for HCC with TSC1 gene mutation.
    Keywords:  Everolimus; Hepatocellular carcinoma; Mammalian target of rapamycin; Next-generation sequencing; Targeted therapy
    DOI:  https://doi.org/10.1159/000505950
  12. Nat Commun. 2021 May 11. 12(1): 2695
    Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons.
    Sun-Gyun Kim, Suho Lee, Yangsik Kim, Jieun Park, Doyeon Woo, Dayeon Kim, Yan Li, Wangyong Shin, Hyunjeong Kang, Chaehyun Yook, Minji Lee, Kyungdeok Kim, Junyeop Daniel Roh, Jeseung Ryu, Hwajin Jung, Seung Min Um, Esther Yang, Hyun Kim, Jinju Han, Won Do Heo, Eunjoon Kim.
      mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.
    DOI:  https://doi.org/10.1038/s41467-021-22908-4
  13. Front Cell Dev Biol. 2021 ;9 667311
    Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways.
    Josué M J Ramirez Reyes, Rafael Cuesta, Arnim Pause.
      Folliculin (FLCN) is a tumor suppressor gene responsible for the inherited Birt-Hogg-Dubé (BHD) syndrome, which affects kidneys, skin and lungs. FLCN is a highly conserved protein that forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2). Although its sequence does not show homology to known functional domains, structural studies have determined a role of FLCN as a GTPase activating protein (GAP) for small GTPases such as Rag GTPases. FLCN GAP activity on the Rags is required for the recruitment of mTORC1 and the transcriptional factors TFEB and TFE3 on the lysosome, where mTORC1 phosphorylates and inactivates these factors. TFEB/TFE3 are master regulators of lysosomal biogenesis and function, and autophagy. By this mechanism, FLCN/FNIP complex participates in the control of metabolic processes. AMPK, a key regulator of catabolism, interacts with FLCN/FNIP complex. FLCN loss results in constitutive activation of AMPK, which suggests an additional mechanism by which FLCN/FNIP may control metabolism. AMPK regulates the expression and activity of the transcriptional cofactors PGC1α/β, implicated in the control of mitochondrial biogenesis and oxidative metabolism. In this review, we summarize our current knowledge of the interplay between mTORC1, FLCN/FNIP, and AMPK and their implications in the control of cellular homeostasis through the transcriptional activity of TFEB/TFE3 and PGC1α/β. Other pathways and cellular processes regulated by FLCN will be briefly discussed.
    Keywords:  AMPK; PGC1α; TFE3; TFEB; folliculin; mTORC1; metabolism; transcriptional regulation
    DOI:  https://doi.org/10.3389/fcell.2021.667311
  14. Autophagy. 2021 May 12. 1-11
    V-ATPase controls tumor growth and autophagy in a Drosophila model of gliomagenesis.
    Miriam Formica, Alessandra Maria Storaci, Irene Bertolini, Francesca Carminati, Helene Knævelsrud, Valentina Vaira, Thomas Vaccari.
      Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of phosphoinositide 3-kinase (PI3K). To understand the role of autophagy in the pathogenesis of glial tumors in vivo, we used an established Drosophila melanogaster model of glioma based on overexpression in larval glial cells of an active human EGFR and of the PI3K homolog Pi3K92E/Dp110. Interestingly, the resulting hyperplastic glia express high levels of key components of the lysosomal-autophagic compartment, including vacuolar-type H+-ATPase (V-ATPase) subunits and ref(2)P (refractory to Sigma P), the Drosophila homolog of SQSTM1/p62. However, cellular clearance of autophagic cargoes appears inhibited upstream of autophagosome formation. Remarkably, downregulation of subunits of V-ATPase, of Pdk1, or of the Tor (Target of rapamycin) complex 1 (TORC1) component raptor prevents overgrowth and normalize ref(2)P levels. In addition, downregulation of the V-ATPase subunit VhaPPA1-1 reduces Akt and Tor-dependent signaling and restores clearance. Consistent with evidence in flies, neurospheres from patients with high V-ATPase subunit expression show inhibition of autophagy. Altogether, our data suggest that autophagy is repressed during glial tumorigenesis and that V-ATPase and MTORC1 components acting at lysosomes could represent therapeutic targets against GBM.
    Keywords:  Autophagy; V-ATPase; cancer model; fruit fly; glioblastoma; lysosomes; neurospheres; ref(2)P
    DOI:  https://doi.org/10.1080/15548627.2021.1918915
  15. Mol Psychiatry. 2021 May 14.
    mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain.
    Radhika Chadha, Khaled Alganem, Robert E Mccullumsmith, James H Meador-Woodruff.
      The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41380-021-01135-9
  16. Clin Cancer Res. 2021 May 13. pii: clincanres.1508.2021. [Epub ahead of print]
    Did Everolimus Break the Rules?
    Shumei Kato, Ezra E W Cohen.
      A phase II study with everolimus (mTORC1 inhibitor) among advanced solid tumors patients with TSC1/TSC2 or MTOR alterations was recently published. Although efficacy was limited, the study provided the future groundwork to advance the targeted therapy approach.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1508
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