bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022‒08‒21
seven papers selected by
Marti Cadena Sandoval
Columbia University
  1. Advances in the genetics and neuropathology of tuberous sclerosis complex: edging closer to targeted therapy.
  2. AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1.
  3. A clinical challenge case of bilateral giant renal angiomyolipoma associated with tuberous sclerosis complex.
  4. Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly.
  5. TBK1-mTOR Signaling Attenuates Obesity-Linked Hyperglycemia and Insulin Resistance.
  6. Proximity labeling of endogenous RICTOR identifies mTOR Complex 2 regulation by ADP ribosylation factor ARF1.
  7. TSC/MTOR-associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum: A Targeted Next-generation Sequencing and Gene Expression Profiling Study.
  1. Lancet Neurol. 2022 09;pii: S1474-4422(22)00213-7. [Epub ahead of print]21(9): 843-856
    Advances in the genetics and neuropathology of tuberous sclerosis complex: edging closer to targeted therapy.
    Paolo Curatolo, Nicola Specchio, Eleonora Aronica.
      Tuberous sclerosis complex is a rare genetic disease associated with mutations in the TSC1 or TSC2 genes, which cause overactivation of the mTOR complex. In the past 5 years, understanding has increased of the cellular consequences of TSC1 and TSC2 genetic variants and the mTORC1 overactivation in neurons and glial cells and their contribution to network dysfunction. Infants and young children (aged 1-5 years) with tuberous sclerosis complex might now benefit from early assessment of gene variant status and mosaicism. In the past 5 years, substantial advances have also been made in our understanding of mTOR-related neuropathology and the molecular aspects of both epileptogenesis and co-occurring neurodevelopmental disorders. Many potential disease-modifying strategies have been identified, including developments in targeted therapies based on molecular findings in epilepsy. Reliable EEG and MRI biomarkers are now available to identify, at a younger age than previously possible, infants with tuberous sclerosis complex who are at risk of epilepsy, autism, and developmental delay. Vigabatrin has been used successfully as a treatment in infants with tuberous sclerosis complex who showed abnormalities on EEG before seizure onset. The scope for mitigation of tuberous sclerosis complex-associated symptoms has expanded, including the use of mTOR inhibitors such as sirolimus and everolimus. Close cooperation between clinical and basic neuroscientists has provided new opportunities for future advances.
    DOI:  https://doi.org/10.1016/S1474-4422(22)00213-7
  2. Nat Commun. 2022 Aug 17. 13(1): 4836
    AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1.
    George K E Umanah, Leire Abalde-Atristain, Mohammed Repon Khan, Jaba Mitra, Mohamad Aasif Dar, Melissa Chang, Kavya Tangella, Amy McNamara, Samuel Bennett, Rong Chen, Vasudha Aggarwal, Marisol Cortes, Paul F Worley, Taekjip Ha, Ted M Dawson, Valina L Dawson.
      The mechanistic target of rapamycin (mTOR) signals through the mTOR complex 1 (mTORC1) and the mTOR complex 2 to maintain cellular and organismal homeostasis. Failure to finely tune mTOR activity results in metabolic dysregulation and disease. While there is substantial understanding of the molecular events leading mTORC1 activation at the lysosome, remarkably little is known about what terminates mTORC1 signaling. Here, we show that the AAA + ATPase Thorase directly binds mTOR, thereby orchestrating the disassembly and inactivation of mTORC1. Thorase disrupts the association of mTOR to Raptor at the mitochondria-lysosome interface and this action is sensitive to amino acids. Lack of Thorase causes accumulation of mTOR-Raptor complexes and altered mTORC1 disassembly/re-assembly dynamics upon changes in amino acid availability. The resulting excessive mTORC1 can be counteracted with rapamycin in vitro and in vivo. Collectively, we reveal Thorase as a key component of the mTOR pathway that disassembles and thus inhibits mTORC1.
    DOI:  https://doi.org/10.1038/s41467-022-32365-2
  3. Urology. 2022 Aug 10. pii: S0090-4295(22)00682-3. [Epub ahead of print]
    A clinical challenge case of bilateral giant renal angiomyolipoma associated with tuberous sclerosis complex.
    Guixing Tang, Zhiyong Li, Zhiling Zhang, Cheng Luo, Pei Dong.
      
    DOI:  https://doi.org/10.1016/j.urology.2022.07.046
  4. Nat Commun. 2022 Aug 17. 13(1): 4848
    Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly.
    Edoardo Ratto, S Roy Chowdhury, Nora S Siefert, Martin Schneider, Marten Wittmann, Dominic Helm, Wilhelm Palm.
      Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes. When mTORC1 is active, peripheral V-ATPase V1 domains reside in the cytosol where they are stabilized by association with the chaperonin TRiC. Consequently, most lysosomes display low catabolic activity. When mTORC1 activity declines, V-ATPase V1 domains move to membrane-integral V-ATPase Vo domains at lysosomes to assemble active proton pumps. The resulting drop in luminal pH increases protease activity and degradation of protein contents throughout the lysosomal population. These results uncover a principle by which cells rapidly respond to changes in their nutrient environment by mobilizing the latent catabolic capacity of lysosomes.
    DOI:  https://doi.org/10.1038/s41467-022-32515-6
  5. Diabetes. 2022 Aug 19. pii: db220256. [Epub ahead of print]
    TBK1-mTOR Signaling Attenuates Obesity-Linked Hyperglycemia and Insulin Resistance.
    Cagri Bodur, Dubek Kazyken, Kezhen Huang, Aaron Seth Tooley, Kae Won Cho, Tammy M Barnes, Carey N Lumeng, Martin G Myers, Diane C Fingar.
      The innate immune kinase TBK1 (TANK-binding kinase 1) responds to microbial-derived signals to initiate responses against viral and bacterial pathogens. More recent work implicates TBK1 in metabolism and tumorigenesis. The kinase mTOR (mechanistic target of rapamycin) integrates diverse environmental cues to control fundamental cellular processes. Our prior work demonstrated in cells that TBK1 phosphorylates mTOR (on S2159) to increase mTORC1 and mTORC2 catalytic activity and signaling. Here we investigate a role for TBK1-mTOR signaling in control of glucose metabolism in vivo. We find that diet induced obese (DIO) but not lean mice bearing a whole-body "TBK1 resistant" Mtor S2159A knockin allele (MtorA/A) display exacerbated hyperglycemia and systemic insulin resistance with no change in energy balance. Mechanistically, Mtor S2159A knockin in DIO mice reduces mTORC1 and mTORC2 signaling in response to insulin and innate immune agonists, reduces anti-inflammatory gene expression in adipose tissue, and blunts anti-inflammatory macrophage M2 polarization, phenotypes shared by mice with tissue-specific inactivation of TBK1 or mTOR complexes. Tissues from DIO mice display elevated TBK1 activity and mTOR S2159 phosphorylation relative to lean mice. We propose a model whereby obesity-associated signals increase TBK1 activity and mTOR phosphorylation, which boosts mTORC1 and mTORC2 signaling in parallel to the insulin pathway, thereby attenuating insulin resistance to improve glycemic control during diet-induced obesity.
    DOI:  https://doi.org/10.2337/db22-0256
  6. J Biol Chem. 2022 Aug 13. pii: S0021-9258(22)00822-5. [Epub ahead of print] 102379
    Proximity labeling of endogenous RICTOR identifies mTOR Complex 2 regulation by ADP ribosylation factor ARF1.
    Amelia K Luciano, Ekaterina Korobkina, Scott P Lyons, John A Haley, Shelagh Fluharty, Su Myung Jung, Arminja N Kettenbach, David A Guertin.
      Mechanistic Target of Rapamycin (mTOR) complex 2 (mTORC2) regulates metabolism, cell proliferation, and cell survival. mTORC2 activity is stimulated by growth factors, and it phosphorylates the hydrophobic motif site of the AGC kinases AKT, SGK, and PKC. However, the proteins that interact with mTORC2 to control its activity and localization remain poorly defined. To identify mTORC2 interacting proteins in living cells, we tagged endogenous RICTOR, an essential mTORC2 subunit, with the modified BirA biotin ligase BioID2 and performed live-cell proximity labeling. We identified 215 RICTOR-proximal proteins, including proteins with known mTORC2 pathway interactions, and 135 proteins (63%) not previously linked to mTORC2 signaling, including nuclear and cytoplasmic proteins. Our imaging and cell fractionation experiments suggest nearly 30% of RICTOR is in the nucleus, hinting at potential nuclear functions. We also identified 29 interactors containing RICTOR-dependent, insulin-stimulated phosphorylation sites, thus providing insight into mTORC2-dependent insulin signaling dynamics. Finally, we identify the endogenous ADP ribosylation factor 1 (ARF1) GTPase as an mTORC2-interacting protein. Through gain- and loss-of-function studies, we provide functional evidence that ARF1 may negatively regulate mTORC2. In summary, we present a new method of studying endogenous mTORC2, a resource of RICTOR/mTORC2 protein interactions in living cells, and a potential mechanism of mTORC2 regulation by the ARF1 GTPase.
    Keywords:  ADP ribosylation factor (ARF); Akt/PKB; BioID2; RICTOR; cell signaling; growth factor; mTORC2; mammalian target of rapamycin (mTOR); proximity labeling
    DOI:  https://doi.org/10.1016/j.jbc.2022.102379
  7. Am J Surg Pathol. 2022 Aug 19.
    TSC/MTOR-associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum: A Targeted Next-generation Sequencing and Gene Expression Profiling Study.
    Qiu-Yuan Xia, Xiao-Tong Wang, Ming Zhao, Hui-Ying He, Ru Fang, Sheng-Bing Ye, Rui Li, Xuan Wang, Ru-Song Zhang, Zhen-Feng Lu, Heng-Hui Ma, Zi-Yu Wang, Qiu Rao.
      BACKGROUND: Several TSC1/2- or MTOR-mutated eosinophilic renal tumor subsets are emerging, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumors (EVTs) and low-grade oncocytic tumors (LOTs). "Unclassified renal tumors with TSC/MTOR mutations" (TSC-mt RCC-NOS) do not meet the criteria for other histomolecular subtypes. Whether these tumors represent a continuum of 1 TSC/MTOR-mutation-associated disease is unknown.DESIGN: We evaluated the clinicopathologic and IHC profiles of 39 eosinophilic renal tumors with targeted DNA sequencing-confirmed TSC/MTOR mutations. Twenty-eight of these, plus 6 ChRCC, 5 RO, 5 ccRCC, 7 MiT RCC and 6 normal renal tissues, were profiled transcriptionally by RNA-seq.
    RESULTS: The 39 cases were reclassified based on morphological and IHC features as ESC RCC (12), EVT (9), LOT, (8) and TSC-mt RCC-NOS (10). The mutation profiles demonstrated consistency; ESC RCCs (12/12) had TSC mutations, and most LOTs (7/8) had MTOR mutations. Ten TSC-mt RCC-NOSs exhibited heterogeneous morphology, arising a differential diagnosis with other renal tumors, including MiT RCC, PRCC and epithelioid PEComa. RNA sequencing-based clustering segregated ESC RCC, EVT and LOT from each other and other renal tumors, indicating expression profile-level differences. Most TSC-mt RCC-NOSs (6/7) formed a mixed cluster with ESC RCC, indicating similar expression signatures; one TSC-mt RCC-NOS with unusual biphasic morphology clustered with EVT.
    CONCLUSIONS: We expanded the TSC/MTOR-associated eosinophilic renal tumor morphologic spectrum, identified gene mutation characteristics, and highlighted differential diagnosis challenges, especially with MiT RCC. ESC RCC, EVT, and LOT having distinct expression profiles. TSC-mt RCC-NOS may cluster with recognized TSC/MTOR-associated entities.
    DOI:  https://doi.org/10.1097/PAS.0000000000001955
This page is being maintained by Thomas Krichel. It was last updated on 2022‒10‒04 at 13:41:03.