bims-tubesc 2023-03-05 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2023‒03‒05
eight papers selected by
Marti Cadena Sandoval
Columbia University

Tuberous Sclerosis Complex: Prenatal Diagnosis Using Ultrasound and Magnetic Resonance Imaging-A Report of Two Cases.
Concurrent diagnoses of Tuberous sclerosis and multiple sclerosis.
Long-term dietary DHA intervention prevents telomere attrition and lipid disturbance in telomerase-deficient male mice.
mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.
MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1.
LAMTOR1 ubiquitination restricts its interaction with the vacuolar-type H+-ATPase, promotes autophagy and is controlled by USP32.
Lysosomal control of senescence and inflammation through cholesterol partitioning.
Everolimus as a therapeutic option in refractory epilepsy in children with tuberous sclerosis: a systematic review.

Indian J Radiol Imaging. 2023 Jan;33(1): 113-116

Tuberous Sclerosis Complex: Prenatal Diagnosis Using Ultrasound and Magnetic Resonance Imaging-A Report of Two Cases.

Eduardo Félix Martins Santana, Ana Maria Faria Esteves, Daniella Guerra Delorenzo, Celso Hygino, Heron Werner, Edward Araujo Júnior.

  Tuberous sclerosis complex (TSC) is a multiple system neurocutaneous syndrome with a genetic disorder caused by different mutations in TSC1 or TSC2. Usually, TSC causes tumors in the heart, brain, kidneys, eyes, and lungs. However, tumors can also develop in any other organs. The prenatal diagnosis of TCS is based on the identification of fetal cardiac tumors by ultrasound and brain subependymal nodules, usually identified by fetal magnetic resonance imaging (MRI). We present two case reports of the prenatal diagnosis of TCS using both ultrasound and MRI, which were confirmed by clinical and radiological methods in the postnatal period accordingly.

Keywords:  magnetic resonance imaging; prenatal diagnosis; tuberous sclerosis complex; ultrasound

DOI:  https://doi.org/10.1055/s-0042-1758196
Mult Scler Relat Disord. 2023 Feb 18. pii: S2211-0348(23)00090-1. [Epub ahead of print]71 104586

Concurrent diagnoses of Tuberous sclerosis and multiple sclerosis.

Suzanne Quigley, Murva Asad, Colin Doherty, Danielle Byrne, Simon Cronin, Hugh Kearney.

  Tuberous sclerosis (TS) is a monogenic disorder which causes disabling neurological symptoms. Similarly, multiple sclerosis (MS) may result in disability, but in contrast, is diagnosed without genetic testing. Clinicians are advised to exercise caution in diagnosing MS in the presence of a pre-existing genetic disorder, as it may be a potential 'red flag'. A dual diagnosis of MS and TS has not previously been reported in the literature. We provide two cases of known cases of TS who presented with new neurological symptoms and associated physical signs compatible with a dual diagnosis of TS/MS.

Keywords:  Multiple sclerosis; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.msard.2023.104586
Eur J Nutr. 2023 Mar 01.

Long-term dietary DHA intervention prevents telomere attrition and lipid disturbance in telomerase-deficient male mice.

Jingnan Chen, Shanyun Wu, Yuqi Wu, Pan Zhuang, Yu Zhang, Jingjing Jiao.

  PURPOSE: Previous evidence indicated anti-ageing potential of docosahexaenoic acid (DHA), but the underlying mechanism remains unclear. We investigated protective effect of DHA on telomere attrition and lipid disturbance in male mice with premature ageing caused by telomerase deficiency.METHODS: Wild-type (WT) and fourth-generation telomerase-deficient (G4 Terc-/-, Terc knockout, KO) male mice (C57BL/6, 2 months old) were fed control diet (WT-C and KO-C groups) or DHA-enriched diet containing 0.80% DHA by weight (WT-DHA and KO-DHA groups) for 10 months. The ageing phenotypes and metabolic level [carbon dioxide emission, oxygen consumption, and respiratory exchange ratio (RER)] were assessed at the end of the experiment. Telomere length in various tissues and the hepatic gene and protein expression for regulating lipid synthesis and lipolysis were measured. Data were tested using one- or two-factor ANOVA.
RESULTS: In KO male mice, DHA prevented weight loss, corrected high RER, and reduced fat loss. Telomere shortening was reduced by 22.3%, 25.5%, and 13.5% in heart, liver, and testes of the KO-DHA group compared with those in the KO-C group. The KO-DHA group exhibited higher gene transcription involved in glycerol-3-phosphate pathway [glycerol-3-phosphate acyltransferase (Gpat)], lower gene expression of β-oxidation [carnitine palmitoyltransferase 1a (Cpt1a)], and upregulation of proteins in lipid synthesis [mammalian target of rapamycin complex 1 (mTORC1) and sterol responsive element binding protein 1 (SREBP1)] in liver than the KO-C group.
CONCLUSION: Long-term DHA intervention attenuates telomere attrition and promotes lipid synthesis via the tuberous sclerosis complex 2 (TSC2)-mTORC1-SREBP1 pathway in KO male mice.

Keywords:  Anti-ageing; DHA; Lipid synthesis; Telomere attrition; mTORC1

DOI:  https://doi.org/10.1007/s00394-023-03120-0
Nat Commun. 2023 Mar 03. 14(1): 1214

mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.

Heng-Jia Liu, Heng Du, Damir Khabibullin, Mahsa Zarei, Kevin Wei, Gordon J Freeman, David J Kwiatkowski, Elizabeth P Henske.

Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38+CD39+CD4+ T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38+CD39+CD4+ T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4+ T cells.

DOI: https://doi.org/10.1038/s41467-023-36881-7
Biochim Biophys Acta Mol Cell Res. 2023 Feb 28. pii: S0167-4889(23)00020-4. [Epub ahead of print]1870(4): 119449

MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1.

Sheikh Tahir Majeed, Rabiya Majeed, Aijaz A Malik, Khurshid Iqbal Andrabi.

  Ribosomal protein S6 kinase 1 (S6K1), a major downstream effector molecule of mTORC1, regulates cell growth and proliferation by modulating protein translation and ribosome biogenesis. We have recently identified eIF4E as an intermediate in transducing signals from mTORC1 to S6K1 and further demonstrated that the role of mTORC1 is restricted to inducing eIF4E phosphorylation and interaction with S6K1. This interaction relieves S6K1 auto-inhibition and facilitates its hydrophobic motif (HM) phosphorylation and activation as a consequence. These observations underscore a possible involvement of mTORC1 independent kinase in mediating HM phosphorylation. Here, we report mTORC2 as an in-vivo/physiological HM kinase of S6K1. We show that rapamycin-resistant S6K1 truncation mutant ∆NH∆CT continues to display HM phosphorylation with selective sensitivity toward Torin-1. We also show that HM phosphorylation of wildtype S6K1and ∆NH∆CT depends on the presence of mTORC2 regulatory subunit-rictor. Furthermore, truncation mutagenesis and molecular docking analysis reveal the involvement of a conserved 19 amino acid stretch of S6K1 in mediating interaction with rictor. We finally show that deletion of the 19 amino acid region from wildtype S6K1 results in loss of interaction with rictor, with a resultant loss of HM phosphorylation regardless of the presence of functional TOS motif. Our data demonstrate that mTORC2 acts as a physiological HM kinase that can activate S6K1 after its auto-inhibition is overcome by mTORC1. We, therefore, propose a novel mechanism for S6K1 regulation where mTOR complexes 1 and 2 act in tandem to activate the enzyme.

Keywords:  Hydrophobic motif; Kinase; Rapamycin; S6 Kinase 1; Torin; eIF4E; mTORC1; mTORC2

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119449
Autophagy. 2023 Mar 01. 1-2

LAMTOR1 ubiquitination restricts its interaction with the vacuolar-type H+-ATPase, promotes autophagy and is controlled by USP32.

Alexandra Hertel, Stefan Eimer, Anja Bremm.

  Among the various signals governing autophagy, ubiquitination plays a critical role both by controlling the stability of upstream regulators or components of macroautophagy/autophagy pathways and by facilitating the recruitment of cargo to autophagy receptors. As such, modulators of ubiquitin signaling can influence autophagic substrate degradation. Recently, we identified a non-proteolytic ubiquitin signal at the Ragulator complex subunit LAMTOR1 that is reversed by the deubiquitinase USP32. Loss of USP32 promotes ubiquitination within the unstructured N-terminal region of LAMTOR1 and prevents its efficient interaction with the vacuolar-type H+-ATPase, a prerequisite for full activation of MTORC1 at lysosomes. Consequently, MTORC1 activity is decreased and autophagy is upregulated in USP32 knockout cells. This phenotype is conserved in Caenorhabditis elegans. Depletion of USP32 homolog CYK-3 in worms results in LET-363/MTOR inhibition and autophagy induction. Based on our data, we propose an additional control layer of the MTORC1 activation cascade at lysosomes via USP32-regulated LAMTOR1 ubiquitination.

Keywords:  ATPase; LAMTOR1; USP32; V-MTORC1; autophagy; deubiquitinase (DUB); ragulator complex; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2023.2184958
Nat Metab. 2023 Mar 02.

Lysosomal control of senescence and inflammation through cholesterol partitioning.

Kyeonghwan Roh, Jeonghwan Noh, Yeonju Kim, Yeji Jang, Jaejin Kim, Haebeen Choi, Yeonghyeon Lee, Moongi Ji, Donghyun Kang, Mi-Sung Kim, Man-Jeong Paik, Jongkyeong Chung, Jin-Hong Kim, Chanhee Kang.

Whereas cholesterol is vital for cell growth, proliferation, and remodeling, dysregulation of cholesterol metabolism is associated with multiple age-related pathologies. Here we show that senescent cells accumulate cholesterol in lysosomes to maintain the senescence-associated secretory phenotype (SASP). We find that induction of cellular senescence by diverse triggers enhances cellular cholesterol metabolism. Senescence is associated with the upregulation of the cholesterol exporter ABCA1, which is rerouted to the lysosome, where it moonlights as a cholesterol importer. Lysosomal cholesterol accumulation results in the formation of cholesterol-rich microdomains on the lysosomal limiting membrane enriched with the mammalian target of rapamycin complex 1 (mTORC1) scaffolding complex, thereby sustaining mTORC1 activity to support the SASP. We further show that pharmacological modulation of lysosomal cholesterol partitioning alters senescence-associated inflammation and in vivo senescence during osteoarthritis progression in male mice. Our study reveals a potential unifying theme for the role of cholesterol in the aging process through the regulation of senescence-associated inflammation.

DOI: https://doi.org/10.1038/s42255-023-00747-5
Arq Neuropsiquiatr. 2023 Mar 02.

Everolimus as a therapeutic option in refractory epilepsy in children with tuberous sclerosis: a systematic review.

Catarina Ester Gomes Menezes, Débora Lopes Dos Santos, Erick Santos Nery, Evelin Duarte Serpa, Lécio Aragão Souza Morais, Lucas Santana Dutra, Marcos Baruch Portela Filho, Julieta Sobreira Goes.

BACKGROUND: Tuberous sclerosis (TS) is a multisystem genetic disease in which epilepsy is a frequent manifestation and is often difficult to control. Everolimus is a drug with proven efficacy in the treatment of other conditions related to TS, and some evidence suggests that its use benefits the treatment of refractory epilepsy in these patients.OBJECTIVE: To evaluate the efficacy of everolimus in controlling refractory epilepsy in children with TS.
METHODS: A literature review was conducted in the Pubmed, BVS, and Medline databases, using the descriptors Tuberous sclerosis, Children, Epilepsy, and Everolimus. Original clinical trials and prospective studies published in Portuguese or English in the last decade that evaluated the use of everolimus as an adjuvant therapy in the control of refractory epilepsy in pediatric patients with TS were included.
RESULTS: Our search screened 246 articles from electronic databases, 6 of which were chosen for review. Despite the methodological variations between the studies, most patients benefited from the use of everolimus to control refractory epilepsy, with response rates ranging from 28.6 to 100%. Adverse effects were present in all studies leading to dropouts of some patients; however, the majority were of low severity.
CONCLUSION: The selected studies suggest a beneficial effect of everolimus in the treatment of refractory epilepsy in children with TS, despite the adverse effects observed. Further studies involving a larger sample in double-blind controlled clinical trials should be performed to provide more information and statistical credibility.

DOI: https://doi.org/10.1055/s-0042-1758442