bims-tubesc 2021-09-19 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–09–19
seventeen papers selected by

UBE2S exerts oncogenic activities in urinary bladder cancer by ubiquitinating TSC1.
Tuberous Sclerosis: Current Update.
Prediction of tuberous sclerosis-associated neurocognitive disorders and seizures via machine learning of structural magnetic resonance imaging.
A Multidisciplinary Approach in Prenatal Diagnosis of TSC With Cardiac Rhabdomyoma as the Initial Symptom.
Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
Patient and Caregiver Health State Utilities in Tuberous Sclerosis Complex.
Eosinophilic Solid and Cystic Renal Cell Carcinoma: From Unclassified to Classified, A Case Report.
Concurrent Angiomyolipoma and Clear Cell Renal Cell Carcinoma in the Same Kidney: A Rare Finding in a Patient without Tuberous Sclerosis.
Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.
Symptomatic Periungual Fibroma of the Hand.
Regulation of human mTOR complexes by DEPTOR.
Targeting the mTOR pathway using novel ATP‑competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma.
Proteomics of autism and Alzheimer's mouse models reveal common alterations in mTOR signaling pathway.
The Development and Survival of Thymic Epithelial Cells Require TSC1-Dependent Negative Regulation of mTORC1 Activity.
Role of mTor signaling for tubular function and disease.
Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.
Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.

Biochem Biophys Res Commun. 2021 Sep 06. pii: S0006-291X(21)01240-7. [Epub ahead of print]578 7-14

UBE2S exerts oncogenic activities in urinary bladder cancer by ubiquitinating TSC1.

Hao Tang, Tong Fang, Meng Ji, Jun-Ping Wang, Le-Le Song, Qiu-Yan Zhang, Jin-Sheng Wu.

  Ubiquitin-conjugating enzyme E2S (UBE2S), an important E2 enzyme in the process of ubiquitination, has exhibited oncogenic activities in various malignant tumors. However, it remains unknown whether UBE2S plays a role in urinary bladder cancer (UBC) development. In the current study, our data confirmed UBE2S upregulation in UBC. In vitro and in vivo experiments demonstrated that UBE2S knockdown resulted in attenuated proliferation and enhanced apoptosis, which was inverse to the phenotypes with UBE2S overexpression. Gain and loss of function assays confirmed that UBE2S exerts oncogenic activities in UBC by mediating the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we discovered that this UBE2S-modulated carcinogenic mechanism was in the consequence of directly targeting tuberous sclerosis 1 (TSC1), which is the upstream inhibitor of mTOR signaling for ubiquitous degradation. Taken together, this study demonstrated that UBE2S is a carcinogen in UBC and promotes UBC progression by ubiquitously degrading TSC1. This consequently mediates the activation of the mTOR pathway, suggesting a potential therapeutic regimen for UBC by targeting the newly identified UBE2S/TSC1/mTOR axis.

Keywords:  Bladder cancer; TSC1; UBE2S; Ubiquitination

DOI:  https://doi.org/10.1016/j.bbrc.2021.08.057
Radiographics. 2021 Sep 17. 210103

Tuberous Sclerosis: Current Update.

Mindy X Wang, Nicole Segaran, Sanjeev Bhalla, Perry J Pickhardt, Meghan G Lubner, Venkata S Katabathina, Dhakshinamoorthy Ganeshan.

Tuberous sclerosis complex (TSC) is a relatively rare autosomal dominant neurocutaneous disorder secondary to mutations in the TSC1 or TSC2 tumor suppressor genes. Although manifestation of the classic triad of seizures, intellectual disability, and facial angio-fibromas may facilitate timely diagnosis of TSC, the multisystem features that may indicate TSC in the absence of these manifestations remain highly variable. In addition, patients with TSC are at risk of developing multiple benign and malignant tumors in various organ systems, resulting in increased morbidity and mortality. Thus, imaging plays a critical role in diagnosis, surveillance, and management of patients with TSC. It is crucial that radiologists be familiar with TSC and the various associated imaging features to avoid a delayed or incorrect diagnosis. Key manifestations include cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyomas, lymphangioleiomyomatosis, and angiomyolipomas. Renal angiomyolipomas in particular can manifest with imaging features that mimic renal malignancy and pose a diagnostic dilemma. Other manifestations include dermatologic and ophthalmic manifestations, renal cysts, renal cell carcinomas, multifocal micronodular pneumocyte hyperplasia, splenic hamartomas, and other rare tumors such as perivascular epithelioid tumors. In addition to using imaging and clinical features to confirm the diagnosis, genetic testing can be performed. In this article, the molecular pathogenesis, clinical manifestations, and imaging features of TSC are reviewed. Current recommendations for management and surveillance of TSC are discussed as well. ©RSNA, 2021.

DOI: https://doi.org/10.1148/rg.2021210103
Neuroradiology. 2021 Sep 16.

Prediction of tuberous sclerosis-associated neurocognitive disorders and seizures via machine learning of structural magnetic resonance imaging.

Shai Shrot, Philip Lawson, Omer Shlomovitz, Chen Hoffmann, Anat Shrot, Bruria Ben-Zeev, Michal Tzadok.

   PURPOSE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by multiorgan hamartomas, including cerebral lesions, with seizures as a common presentation. Most TSC patients will also experience neurocognitive comorbidities. Our objective was to use machine learning techniques incorporating clinical and imaging data to predict the occurrence of major neurocognitive disorders and seizures in TSC patients.
METHODS: A cohort of TSC patients were enrolled in this retrospective study. Clinical data included genetic, demographic, and seizure characteristics. Imaging parameters included the number, characteristics, and location of cortical tubers and the presence of subependymal nodules, SEGAs, and cerebellar tubers. A random forest machine learning scheme was used to predict seizures and neurodevelopmental delay or intellectual developmental disability. Prediction ability was assessed by the area-under-the-curve of receiver-operating-characteristics (AUC-ROC) of ten-fold cross-validation training set and an independent validation set.
RESULTS: The study population included 77 patients, 55% male (17.1 ± 11.7 years old). The model achieved AUC-ROC of 0.72 ± 0.1 and 0.68 in the training and internal validation datasets, respectively, for predicting neurocognitive comorbidity. Performance was limited in predicting seizures (AUC-ROC of 0.54 ± 0.19 and 0.71 in the training and internal validation datasets, respectively). The integration of seizure characteristics into the model improved the prediction of neurocognitive comorbidity with AUC-ROC of 0.84 ± 0.07 and 0.75 in the training and internal validation datasets, respectively.
CONCLUSIONS: This proof of concept study shows that it is possible to achieve a reasonable prediction of major neurocognitive morbidity in TSC patients using structural brain imaging and machine learning techniques. These tools can help clinicians identify subgroups of TSC patients with an increased risk of developing neurocognitive comorbidities.

Keywords:  Machine learning; Random forest; Seizure; Tuberous sclerosis complex

DOI:  https://doi.org/10.1007/s00234-021-02789-6
Front Pediatr. 2021 ;9 628238

A Multidisciplinary Approach in Prenatal Diagnosis of TSC With Cardiac Rhabdomyoma as the Initial Symptom.

Yiming Qi, Hongke Ding, Yanlin Huang, Yukun Zeng, Lihua Yu, Ling Liu, Yan Zhang, Aihua Yin.

  The long-term prognosis of a fetus with cardiac rhabdomyoma (CR) depends on the correlation with tuberous sclerosis complex (TSC). In recent years, the numerous variations of uncertain significance (VUS) of TSC genes produced by high-throughput sequencing have made counseling challenging, studies until now have tended to side-step the tricky topics. Here, we integrated detailed parental phenotype, echocardiography, neuro MRI, and genetic information to conduct a comprehensive evaluation of 61 CR fetuses. As a result, multiple CRs and cerebral lesions appeared in 90 and 80%, respectively of fetuses with pathogenic (P)/likely pathogenic (LP) TSC1/TSC2 variations. Overall, 85.7% of the live-born infants with P/LP presented with TSC-associated signs. While, 85.7% of VUS without nervous findings had good prognoses. Genetic evidence and cerebral MRI findings are the most sensitive index to assess long-term prognosis, which complement and confirm each other for a TSC diagnosis. In total, 68.9% of fetuses with CR could benefit from this multidisciplinary approach, which turned out to be potentially clinically actionable with precise clinical/genetic diagnosis or had a foreseeable outcome. Our practice provides a practical and feasible solution for perinatal management and prognostic guidance for fetuses with CR.

Keywords:  cardiac rhabdomyoma; fetal tumor; prenatal diagnoses; targeted exome capture sequencing; tuberous sclerosis (TSC)

DOI:  https://doi.org/10.3389/fped.2021.628238
PLoS Comput Biol. 2021 Sep 16. 17(9): e1008513

Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.

Milad Ghomlaghi, Guang Yang, Sungyoung Shin, David E James, Lan K Nguyen.

The PI3K/MTOR signalling network regulates a broad array of critical cellular processes, including cell growth, metabolism and autophagy. The mechanistic target of rapamycin (MTOR) kinase functions as a core catalytic subunit in two physically and functionally distinct complexes mTORC1 and mTORC2, which also share other common components including MLST8 (also known as GβL) and DEPTOR. Despite intensive research, how mTORC1 and 2 assembly and activity are coordinated, and how they are functionally linked remain to be fully characterized. This is due in part to the complex network wiring, featuring multiple feedback loops and intricate post-translational modifications. Here, we integrate predictive network modelling, in vitro experiments and -omics data analysis to elucidate the emergent dynamic behaviour of the PI3K/MTOR network. We construct new mechanistic models that encapsulate critical mechanistic details, including mTORC1/2 coordination by MLST8 (de)ubiquitination and the Akt-to-mTORC2 positive feedback loop. Model simulations validated by experimental studies revealed a previously unknown biphasic, threshold-gated dependence of mTORC1 activity on the key mTORC2 subunit SIN1, which is robust against cell-to-cell variation in protein expression. In addition, our integrative analysis demonstrates that ubiquitination of MLST8, which is reversed by OTUD7B, is regulated by IRS1/2. Our results further support the essential role of MLST8 in enabling both mTORC1 and 2's activity and suggest MLST8 as a viable therapeutic target in breast cancer. Overall, our study reports a new mechanistic model of PI3K/MTOR signalling incorporating MLST8-mediated mTORC1/2 formation and unveils a novel regulatory linkage between mTORC1 and mTORC2.

DOI: https://doi.org/10.1371/journal.pcbi.1008513
Pharmacoecon Open. 2021 Sep 15.

Patient and Caregiver Health State Utilities in Tuberous Sclerosis Complex.

Siu Hing Lo, Jade Marshall, Hanna Skrobanski, Andrew Lloyd.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multisystem disorder often associated with treatment-resistant epilepsy. Cost-effectiveness analysis for new antiseizure medications typically requires health state utilities (HSUs) that reflect the burden of a given condition.
OBJECTIVE: This study aimed to estimate HSUs, with a focus on valuing the impact of seizure type and seizure frequency on health-related quality of life (HRQL) for patients with TSC and their caregivers.
METHODS: A targeted literature review and qualitative research with healthcare professionals and caregivers informed the development of health state vignettes describing the experience of living with TSC or caring for a child with TSC. Vignettes were evaluated in interviews with the UK general population using the time trade-off (TTO) method.
RESULTS: Sixteen vignettes were developed describing patient HRQL (n = 8) and caregiver HRQL (n = 8). Two hundred interviews were conducted via online video calls due to COVID-19 pandemic restrictions. Two hundred participants evaluated the patient (n = 100) and caregiver (n = 100) health state vignettes. Estimated utility scores varied consistently according to seizure type and seizure frequency. Patient TTO utility scores ranged between -0.234 (highest seizure frequency and multiple seizure types) and 0.725 (seizure-free state). Caregiver TTO utility scores ranged from 0.221 to 0.905.
CONCLUSIONS: Findings highlight the substantial burden of living with TSC and caring for a child with TSC. Patient and caregiver burden was greater for generalised versus focal seizures. The burden was greatest for a combination of both seizure types and worsened with increasing seizure frequency.

DOI: https://doi.org/10.1007/s41669-021-00296-1
Turk Patoloji Derg. 2021 Apr 13.

Eosinophilic Solid and Cystic Renal Cell Carcinoma: From Unclassified to Classified, A Case Report.

Rashim Sharma, Balamurugan Thirunavukkarasu, Poonam Elhence, Mahaveer Singh Rodha, Binit Sureka.

Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a novel tumour with unique morphological and immunohistochemical features. It is a recently described entity after the 2016 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs and is characterised by a solid cystic tumour composed of polygonal cells with voluminous eosinophilic cytoplasm and CK20 positivity. This tumour has uncertain malignant potential and also has an association with tuberous sclerosis complex (TSC). Sarcomatoid differentiation has not been reported in ESC RCC till now. ESC RCC poses a diagnostic challenge as many eosinophilic/oncocytic renal tumours are included in the differentials. We present a case of ESC RCC with sarcomatoid differentiation in an elderly female without any clinical features of TSC and discuss the differential diagnosis of oncocytic renal tumours.

DOI: https://doi.org/10.5146/tjpath.2021.01531
Case Rep Urol. 2021 ;2021 6663369

Concurrent Angiomyolipoma and Clear Cell Renal Cell Carcinoma in the Same Kidney: A Rare Finding in a Patient without Tuberous Sclerosis.

Amal Fekkar, Kaoutar Znati, Fouad Zouaidia, Hafsa Elouazzani, Zakia Bernoussi, Ahmed Jahid.

Synchronous renal cell carcinomas (RCC) and angiomyolipomas (AML) occurring in the same kidney are rare. Cases in the setting of tuberous sclerosis (TS) have been reported in the literature. However, the association of these tumors in the same kidney without TS is even more rare. We report here a case of a clear cell renal cell carcinoma (CCRCC) associated with an AML in the same kidney in a 42 years old female lacking the TS diagnostic criteria. The patient underwent a radical nephrectomy. Six months after surgery, the patient is healthy without signs of tumor recurrence or distant metastasis.

DOI: https://doi.org/10.1155/2021/6663369
Mod Pathol. 2021 Sep 14.

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

Farcaş Mihaela, Gatalica Zoran, Trpkov Kiril, Swensen Jeffrey, Zhou Ming, Alaghehbandan Reza, Sean R Williamson, Magi-Galluzzi Cristina, Anthony J Gill, Tretiakova Maria, Jose I Lopez, Perez Montiel Delia, Sperga Maris, Comperat Eva, Brimo Fadi, Yilmaz Asli, Siadat Farshid, Sangoi Ankur, Gao Yuan, Ptákova Nikola, Kuthi Levente, Pivovarcikova Kristyna, Rogala Joanna, Agaimy Abbas, Hartmann Arndt, Fraune Cristoph, Rychly Boris, Hurnik Pavel, Durcansky Dušan, Bonnert Michael, Gakis Georgios, Michal Michal, Hora Milan, Hes Ondrej.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.

DOI: https://doi.org/10.1038/s41379-021-00923-6
J Hand Microsurg. 2021 Jul;13(3): 173-177

Symptomatic Periungual Fibroma of the Hand.

Camelia Qian Ying Tang, Audrey Qi Xin Chia, Sreedharan Sechachalam.

  Periungual fibromas are benign nodules commonly found on acral digital areas that are commonly associated with tuberous sclerosis. They vary in size and are challenging to treat, with a high recurrence rate. We present a case of a patient with a periungual fibroma, which by virtue of its size, was of functional concern. The intraoperative findings and their implications on the clinical outcome, together with a literature review on other treatment modalities, are also presented.

Keywords:  periungual fibroma; tuberous sclerosis

DOI:  https://doi.org/10.1055/s-0040-1709099
Elife. 2021 09 14. pii: e70871. [Epub ahead of print]10

Regulation of human mTOR complexes by DEPTOR.

Matthias Wälchli, Karolin Berneiser, Francesca Mangia, Stefan Imseng, Louise-Marie Craigie, Edward Stuttfeld, Michael N Hall, Timm Maier.

  The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.

Keywords:  DEPTOR; cancer; cryo-EM; human; mTOR; metabolism; molecular biophysics; signaling; structural biology

DOI:  https://doi.org/10.7554/eLife.70871
Int J Oncol. 2021 Oct;pii: 83. [Epub ahead of print]59(4):

Targeting the mTOR pathway using novel ATP‑competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma.

Anubhav G Amin, Seung Won Jeong, John L Gillick, Tolga Sursal, Raj Murali, Chirag D Gandhi, Meena Jhanwar-Uniyal.

  Mechanistic target of rapamycin (mTOR), which functions via two multiprotein complexes termed mTORC1 and mTORC2, is positioned in the canonical phosphoinositide 3‑kinase‑related kinase (PI3K)/AKT (PI3K/AKT) pathways. These complexes exert their actions by regulating other important kinases, such as 40S ribosomal S6 kinases (S6K), eukaryotic translation initiation factor 4E (elF4E)‑binding protein 1 (4E‑BP1) and AKT, to control cell growth, proliferation, migration and survival in response to nutrients and growth factors. Glioblastoma (GB) is a devastating form of brain cancer, where the mTOR pathway is deregulated due to frequent upregulation of the Receptor Tyrosine Kinase/PI3K pathways and loss of the tumor suppressor phosphatase and tensin homologue (PTEN). Rapamycin and its analogs were less successful in clinical trials for patients with GB due to their incomplete inhibition of mTORC1 and the activation of mitogenic pathways via negative feedback loops. Here, the effects of selective ATP‑competitive dual inhibitors of mTORC1 and mTORC2, Torin1, Torin2 and XL388, are reported. Torin2 exhibited concentration‑dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6KSer235/236 and 4E‑BP1Thr37/46 as well as the mTORC2 substrate AKTSer473 resulting in suppression of tumor cell migration, proliferation and S‑phase entry. Torin1 demonstrated similar effects, but only at higher doses. XL388 suppressed cell proliferation at a higher dose, but failed to inhibit cell migration. Treatment with Torin1 suppressed phosphorylation of proline rich AKT substrate of 40 kDa (PRAS40) at Threonine 246 (PRAS40Thr246) whereas Torin2 completely abolished it. XL388 treatment suppressed the phosphorylation of PRAS40Thr246 only at higher doses. Drug resistance analysis revealed that treatment of GB cells with XL388 rendered partial drug resistance, which was also seen to a lesser extent with rapamycin and Torin1 treatments. However, treatment with Torin2 completely eradicated the tumor cell population. These results strongly suggest that Torin2, compared to Torin1 or XL388, is more effective in suppressing mTORC1 and mTORC2, and therefore in the inhibition of the GB cell proliferation, dissemination and in overcoming resistance to therapy. These findings underscore the significance of Torin2 in the treatment of GB.

Keywords:  PRAS40; Torin1; Torin2; glioblastoma; mTOR; mTOR inhibitors

DOI:  https://doi.org/10.3892/ijo.2021.5263
Transl Psychiatry. 2021 Sep 17. 11(1): 480

Proteomics of autism and Alzheimer's mouse models reveal common alterations in mTOR signaling pathway.

Shira Mencer, Maryam Kartawy, Felix Lendenfeld, Huda Soluh, Manish Kumar Tripathi, Igor Khaliulin, Haitham Amal.

Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

DOI: https://doi.org/10.1038/s41398-021-01578-2
J Immunol. 2021 Sep 17. pii: ji2100463. [Epub ahead of print]

The Development and Survival of Thymic Epithelial Cells Require TSC1-Dependent Negative Regulation of mTORC1 Activity.

Zhanfeng Liang, Qian Zhang, Zhaoqi Zhang, Lina Sun, Xue Dong, Tianxiu Li, Liang Tan, Xubiao Xie, Liguang Sun, Yong Zhao.

Thymic epithelial cells (TECs) are critical for the development and generation of functionally competent T cells. Until now, the mechanism that regulates the survival of TECs is poorly understood. In the current study, we found that Tsc1 controls the homeostasis of medullary TECs (mTECs) by inhibiting lysosomal-mediated apoptosis pathway in mice. TEC-specific deletion of Tsc1 predominately decreased the cell number of mTECs and, to a lesser content, affected the development cortical TECs. The defect of mTECs caused by Tsc1 deficiency in mice impaired thymocyte development and peripheral T cell homeostasis. Mechanistically, Tsc1 deficiency did not affect the cell proliferation of mTECs but increased the apoptosis of mTECs significantly. RNA-sequencing analysis showed that pathways involved in lysosomal biogenesis, cell metabolism, and apoptosis were remarkably elevated in Tsc1-deficient mTECs compared with their wild-type counterparts. Tsc1-deficient mTECs exhibited overproduction of reactive oxygen species and malfunction of lysosome, with lysosome membrane permeabilization and the release of cathepsin B and cathepsin L to the cytosol, which then lead to Bid cleaved into active truncated Bid and subsequently intrinsic apoptosis. Finally, we showed that the impaired development of mTECs could be partially reversed by decreasing mTORC1 activity via haploinsufficiency of Raptor Thus, Tsc1 is essential for the homeostasis of mTECs by inhibiting lysosomal-mediated apoptosis through mTORC1-dependent pathways.

DOI: https://doi.org/10.4049/jimmunol.2100463
Physiology (Bethesda). 2021 Sep 13.

Role of mTor signaling for tubular function and disease.

Florian Grahammer, Tobias B Huber, Ferruh Artunc.

  The mechanistic target of rapamycin (mTOR) forms two distinct intracellular multiprotein complexes that control a multitude of intracellular processes linked to metabolism, proliferation, actin cytoskeleton and survival. Recent studies have identified the importance of these complexes for transport regulation of ions and nutrients along the entire nephron. First reports could link altered activity of these complexes to certain disease entities i.e. diabetic nephropathy, AKI or hyperkalemia.

Keywords:  ENaC; RomK; endocytosis; mTOR; proximal tubule

DOI:  https://doi.org/10.1152/physiol.00021.2021
Elife. 2021 09 14. pii: e68799. [Epub ahead of print]10

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.

Maren Heimhalt, Alex Berndt, Jane Wagstaff, Madhanagopal Anandapadamanaban, Olga Perisic, Sarah Maslen, Stephen McLaughlin, Conny Wing-Heng Yu, Glenn R Masson, Andreas Boland, Xiaodan Ni, Keitaro Yamashita, Garib N Murshudov, Mark Skehel, Stefan M Freund, Roger L Williams.

  The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR's PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition.

Keywords:  DEPTOR; biochemistry; cancer; chemical biology; cryo-EM; human; mTOR; molecular biophysics; partial inhibition; signal transduction; structural biology

DOI:  https://doi.org/10.7554/eLife.68799
Mod Pathol. 2021 Sep 16.

Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.

Aurélien Morini, Tom Drossart, Marc-Olivier Timsit, Mathilde Sibony, Viorel Vasiliu, Anne-Paule Gimenez-Roqueplo, Judith Favier, Cécile Badoual, Arnaud Mejean, Nelly Burnichon, Virginie Verkarre.

Low-grade oncocytic renal tumor (LOT) is an emerging provisional entity, described as rare solid renal oncocytic/eosinophilic tumor sharing diffuse CK7 and negative CD117 immunoprofile. The links between LOT and other eosinophilic chromophobe like-renal cell carcinomas (RCC) are currently discussed. We sequenced tumoral DNA with a next generation sequencing panel for kidney cancer and carried out immunohistochemical analyses with CK7, CD117, SDHB, 4EBP1-P, S6K-P, and FOXI1 antibodies in a series of ten cases of LOT (9 females, 1 male; mean age at surgery: 66 years, 42.3 to 83.4) retrospectively diagnosed from a cohort of 272 tumors initially classified as chromophobe RCC (CHRCC). All LOT were single, without known hereditary predisposition, classified stage pT1 (70%), pT2 (20%) or pT3a (10%). Morphological features were similar to previous descriptions and clinical behavior was indolent for the six cases with available follow-up. We identified genetic variations in mTOR pathway related genes in 80% of cases, MTOR (7 cases) or TSC1 (1 case). Expression of FOXI1 was absent in all cases. In 9 LOT, 4EBP1-P and S6K-P were overexpressed, suggesting mTOR pathway activation.Our data highlights the major role of mTOR pathway in tumorigenesis of LOT mostly due to activating MTOR gene variations. Absence of FOXI1 expression is a strong argument to distinguish LOT from eosinophilic CHRCC and to bring them closer to other recently described FOXI1 negative eosinophilic-CHRCC like with MTOR/TSC mutations. Altogether, our data argue to consider LOT as a distinct entity with a favorable clinical outcome. However, in case of metastasis, an accurate diagnosis of LOT would be essential for the patient's management and could allow targeted therapy.

DOI: https://doi.org/10.1038/s41379-021-00906-7