bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021–08–15
eleven papers selected by
  1. Correction for Tee et al., Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.
  2. Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.
  3. Distribution of Hypomelanotic Macules in Tuberous Sclerosis Complex: a Retrospective Cohort Study.
  4. Chondrocyte Tsc1 controls cranial base bone development by restraining the premature differentiation of synchondroses.
  5. The zinc finger/RING domain protein Unkempt regulates cognitive flexibility.
  6. Lamin regulates the dietary restriction response via the mTOR pathway in Caenorhabditis elegans.
  7. MTORC1-dependent crinophagy regulates glucagon content in pancreatic α-cells.
  8. Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy.
  9. Sestrins regulate muscle stem cell metabolic homeostasis.
  10. The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis.
  11. Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis.
  1. Proc Natl Acad Sci U S A. 2021 Aug 17. pii: e2112628118. [Epub ahead of print]118(33):
    Correction for Tee et al., Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.
      
    DOI:  https://doi.org/10.1073/pnas.2112628118
  2. Cell Rep. 2021 Aug 10. pii: S2211-1247(21)00941-4. [Epub ahead of print]36(6): 109511
    Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.
    Katelyn N Benthall, Katherine R Cording, Alexander H C W Agopyan-Miu, Corinna D Wong, Emily Y Chen, Helen S Bateup.
      Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.
    Keywords:  Tsc1; Tsc2; Tuberous Sclerosis Complex; autism spectrum disorder; corticostriatal synapses; direct pathway; endocannabinoid-LTD; indirect pathway; motor learning; striatum
    DOI:  https://doi.org/10.1016/j.celrep.2021.109511
  3. J Am Acad Dermatol. 2021 Aug 07. pii: S0190-9622(21)02282-9. [Epub ahead of print]
    Distribution of Hypomelanotic Macules in Tuberous Sclerosis Complex: a Retrospective Cohort Study.
    Aya Takahashi, Satoshi Hattori, Ena Sakai, Lingli Yang, Ichiro Katayama, Manabu Fujimoto, Wataya-Kaneda Mari.
      
    Keywords:  Blaschko’s lines; cutaneous manifestations of tuberous sclerosis complex; distribution of tuberous sclerosis complex; hypomelanotic macule; tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.jaad.2021.07.071
  4. Bone. 2021 Aug 05. pii: S8756-3282(21)00307-0. [Epub ahead of print] 116142
    Chondrocyte Tsc1 controls cranial base bone development by restraining the premature differentiation of synchondroses.
    Yuan-Lynn Hsieh, Xiaoxi Wei, Yating Wang, Honghao Zhang, Shuqun Qi, Di Xie, Yuji Mishina, Daniela Mendonça, Nan Hatch, Fei Liu.
      Cranial base bones are formed through endochondral ossification. Synchondroses are growth plates located between cranial base bones that facilitate anterior-posterior growth of the skull. Coordinated proliferation and differentiation of chondrocytes in cranial base synchondroses is essential for cranial base bone growth. Herein, we report that constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling via Tsc1 (Tuberous sclerosis 1) deletion in chondrocytes causes abnormal skull development with decreased size and rounded shape. In contrast to decreased anterior-posterior growth of the cranial base, mutant mice also exhibited significant expansion of cranial base synchondroses including the intersphenoid synchondrosis (ISS) and the spheno-occipital synchondrosis (SOS). Cranial base synchondrosis expansion in TSC1-deficient mice was accounted for by expansion in the resting zone due to increased cell number and size without alteration in cell proliferation. Furthermore, our data showed that mTORC1 activity is inhibited in the resting and proliferating zone chondrocytes of wild type mice, and Tsc1 deletion activated mTORC1 signaling of the chondrocytes in the resting zone area. Consequently, the chondrocytes in the resting zone of TSC1-deficient mice acquired characteristics generally attributed to pre-hypertrophic chondrocytes including high mTORC1 activity, increased cell size, and increased expression level of PTH1R (Parathyroid hormone 1 receptor) and IHH (Indian hedgehog). Lastly, treatment with rapamycin, an inhibitor of mTORC1, rescued the abnormality in synchondroses. Our results established an important role for TSC1-mTORC1 signaling in regulating cranial base bone development and showed that chondrocytes in the resting zone of synchondroses are maintained in an mTORC1-inhibitory environment.
    Keywords:  ISS; SOS; Tsc1; chondrocyte; cranial base; cranial synchondrosis; endochondral; mTORC1; skull
    DOI:  https://doi.org/10.1016/j.bone.2021.116142
  5. Sci Rep. 2021 Aug 11. 11(1): 16299
    The zinc finger/RING domain protein Unkempt regulates cognitive flexibility.
    Elin Vinsland, Pranetha Baskaran, Simeon R Mihaylov, Carl Hobbs, Hannah Wood, Ihssane Bouybayoune, Kriti Shah, Corinne Houart, Andrew R Tee, Jernej Murn, Cathy Fernandes, Joseph M Bateman.
      Correct orchestration of nervous system development is a profound challenge that involves coordination of complex molecular and cellular processes. Mechanistic target of rapamycin (mTOR) signaling is a key regulator of nervous system development and synaptic function. The mTOR kinase is a hub for sensing inputs including growth factor signaling, nutrients and energy levels. Activation of mTOR signaling causes diseases with severe neurological manifestations, such as tuberous sclerosis complex and focal cortical dysplasia. However, the molecular mechanisms by which mTOR signaling regulates nervous system development and function are poorly understood. Unkempt is a conserved zinc finger/RING domain protein that regulates neurogenesis downstream of mTOR signaling in Drosophila. Unkempt also directly interacts with the mTOR complex I component Raptor. Here we describe the generation and characterisation of mice with a conditional knockout of Unkempt (UnkcKO) in the nervous system. Loss of Unkempt reduces Raptor protein levels in the embryonic nervous system but does not affect downstream mTORC1 targets. We also show that nervous system development occurs normally in UnkcKO mice. However, we find that Unkempt is expressed in the adult cerebellum and hippocampus and behavioural analyses show that UnkcKO mice have improved memory formation and cognitive flexibility to re-learn. Further understanding of the role of Unkempt in the nervous system will provide novel mechanistic insight into the role of mTOR signaling in learning and memory.
    DOI:  https://doi.org/10.1038/s41598-021-95286-y
  6. J Cell Sci. 2021 Aug 12. pii: jcs.258428. [Epub ahead of print]
    Lamin regulates the dietary restriction response via the mTOR pathway in Caenorhabditis elegans.
    Chayki Charar, Sally Metsuyanim-Cohen, Daniel Z Bar.
      Animals subjected to dietary restriction (DR) have reduced body size, low fecundity, slower development, lower fat content and longer life span. We identified lamin as a regulator of multiple dietary restriction phenotypes. Downregulation of lmn-1, the single Caenorhabditis elegans lamin gene, increased animal size and fat content, specifically in DR animals. The LMN-1 protein acts in the mTOR pathway, upstream to RAPTOR and S6K, key component and target of mTOR complex 1 (mTORC1), respectively. DR excludes the mTORC1 activator RAGC-1 from the nucleus. Downregulation of lmn-1 restores RAGC-1 to the nucleus, a necessary step for the activation of the mTOR pathway. These findings further link lamin to metabolic regulation.
    Keywords:  Caenorhabditis elegans; Dietary restriction; Lamin; mTOR
    DOI:  https://doi.org/10.1242/jcs.258428
  7. Autophagy. 2021 Aug 12. 1-2
    MTORC1-dependent crinophagy regulates glucagon content in pancreatic α-cells.
    Sangam Rajak, Paul M Yen, Rohit A Sinha.
      Hormone synthesis and secretion is a highly regulated process governed by metabolic cues. Although peptide hormone action is largely governed by the rate of its synthesis and secretion by endocrine cells, and the levels of its receptors on the target cells, intracellular degradation of the hormone-containing secretory vesicles by lysosomes (crinophagy) adds an additional layer of regulation. In our recent study, we uncovered the regulatory mechanism governing the crinophagic turnover of GCG (glucagon), a glycoprotein hormone secreted by pancreatic α-cells. Our results showed that inhibition of MTORC1 induces crinophagy-mediated degradation of glucagon and decreases its secretion in response to hypoglycemia. Furthermore, we demonstrated that crinophagy-regulated glucagon turnover does not involve macroautophagy. These results suggest that modulation of crinophagy may serve as a novel therapeutic strategy to regulate hormone secretion in endocrine and metabolic pathologies.
    Keywords:  Autophagy; MTORC1; crinophagy; diabetes; glucagon; lysosomes; rapamycin
    DOI:  https://doi.org/10.1080/15548627.2021.1961074
  8. Autophagy. 2021 Aug 12. 1-17
    Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy.
    Kunpeng Liu, Dongbo Qiu, Xue Liang, Yingqi Huang, Yao Wang, Xin Jia, Kun Li, Jingyuan Zhao, Cong Du, Xiusheng Qiu, Jun Cui, Zhendong Xiao, Yunfei Qin, Qi Zhang.
      Lipid accumulation often leads to lipotoxic injuries to hepatocytes, which can cause nonalcoholic steatohepatitis. The association of inflammation with lipid accumulation in liver tissue has been studied for decades; however, key mechanisms have been identified only recently. In particular, it is still unknown how hepatic inflammation regulates lipid metabolism in hepatocytes. Herein, we found that PA treatment or direct stimulation of STING1 promoted, whereas STING1 deficiency impaired, MTORC1 activation, suggesting that STING1 is involved in PA-induced MTORC1 activation. Mechanistic studies revealed that STING1 interacted with several components of the MTORC1 complex and played an important role in the complex formation of MTORC1 under PA treatment. The involvement of STING1 in MTORC1 activation was dependent on SQSTM1, a key regulator of the MTORC1 pathway. In SQSTM1-deficient cells, the interaction of STING1 with the components of MTORC1 was weak. Furthermore, the impaired activity of MTORC1 via rapamycin treatment or STING1 deficiency decreased the numbers of LDs in cells. PA treatment inhibited lipophagy, which was not observed in STING1-deficient cells or rapamycin-treated cells. Restoration of MTORC1 activity via treatment with amino acids blocked lipophagy and LDs degradation. Finally, increased MTORC1 activation concomitant with STING1 activation was observed in liver tissues of nonalcoholic fatty liver disease patients, which provided clinical evidence for the involvement of STING1 in MTORC1 activation. In summary, we identified a novel regulatory loop of STING1-MTORC1 and explain how hepatic inflammation regulates lipid accumulation. Our findings may facilitate the development of new strategies for clinical treatment of hepatic steatosis.Abbreviations: AA: amino acid; ACTB: actin beta; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; DEPTOR: DEP domain containing MTOR interacting protein; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FFAs: free fatty acids; GFP: green fluorescent protein; HFD: high-fat diet; HT-DNA: herring testis DNA; IL1B: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LDs: lipid droplets; MAP1LC3: microtubule associated protein 1 light chain 3; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MLST8: MTOR associated protein, LST8 homolog; MT-ND1: mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NAFL: nonalcoholic fatty liver; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NPCs: non-parenchymal cells; PA: palmitic acid; PLIN2: perilipin 2; RD: regular diet; RELA: RELA proto-oncogene, NF-kB subunit; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RPTOR: regulatory associated protein of MTOR complex 1; RRAGA: Ras related GTP binding A; RRAGC: Ras related GTP binding C; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGs: triglycerides; TREX1: three prime repair exonuclease 1.
    Keywords:  Lipophagy; MTORC1; NAFLD; STING1; TBK1
    DOI:  https://doi.org/10.1080/15548627.2021.1961072
  9. Stem Cell Reports. 2021 Jul 29. pii: S2213-6711(21)00380-5. [Epub ahead of print]
    Sestrins regulate muscle stem cell metabolic homeostasis.
    Benjamin A Yang, Jesus Castor-Macias, Paula Fraczek, Ashley Cornett, Lemuel A Brown, Myungjin Kim, Susan V Brooks, Isabelle M A Lombaert, Jun Hee Lee, Carlos A Aguilar.
      The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. We show that SESTRIN1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle, and shifts in metabolic flux. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging.
    Keywords:  RNA sequencing; aging; mTORC1; metabolism; oxidative stress; reactive oxygen species; regeneration; satellite cells
    DOI:  https://doi.org/10.1016/j.stemcr.2021.07.014
  10. Nat Commun. 2021 Aug 13. 12(1): 4928
    The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis.
    Ting Yuan, Karthika Annamalai, Shruti Naik, Blaz Lupse, Shirin Geravandi, Anasua Pal, Aleksandra Dobrowolski, Jaee Ghawali, Marina Ruhlandt, Kanaka Durga Devi Gorrepati, Zahra Azizi, Dae-Sik Lim, Kathrin Maedler, Amin Ardestani.
      Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.
    DOI:  https://doi.org/10.1038/s41467-021-25145-x
  11. Nat Commun. 2021 08 10. 12(1): 4814
    Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis.
    Clément Bodineau, Mercedes Tomé, Sarah Courtois, Ana S H Costa, Marco Sciacovelli, Benoit Rousseau, Elodie Richard, Pierre Vacher, Carlos Parejo-Pérez, Emilie Bessede, Christine Varon, Pierre Soubeyran, Christian Frezza, Piedad Del Socorro Murdoch, Victor H Villar, Raúl V Durán.
      Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.
    DOI:  https://doi.org/10.1038/s41467-021-25079-4
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