bims-tubesc 2021-11-21 papers

Issue of 2021–11–21
six papers selected by

Front Cell Dev Biol. 2021 ;9 751892

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back.

Ulrike Rehbein, Mirja Tamara Prentzell, Marti Cadena Sandoval, Alexander Martin Heberle, Elizabeth P Henske, Christiane A Opitz, Kathrin Thedieck.

The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes via phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM).

Keywords: G3BP1 (G3BP stress granule assembly factor 1); HDLBP; TSC complex; autophagy; lymphangioleiomyomatosis (LAM); lysosomes; mTORC1 (mechanistic target of rapamycin complex 1); stress granules (SG)

DOI: https://doi.org/10.3389/fcell.2021.751892

Iran J Child Neurol. 2021 ;15(4): 15-25

The Effect of Everolimus on Subependymal Giant Cell Astrocytoma (SEGA) in Children with Tuberous Sclerosis Complex.

Hassan Bakhtiary, Mohammad Barzegar, Shadi Shiva, Bita Poorshiri, Parisa Hajalioghli, Hamideh Herizchi Ghadim.

Objective: Subependymal Giant Cell Astrocytomas (SEGAs) are slow-growing glioneuronal tumors typically found around the ventricles of the brain, particularly near the foramen of Monro in 15%-20% of patients with tuberous sclerosis complex (TSC). Surgical resection is the standard treatment for these symptomatic tumors. The mTOR inhibitor everolimus can be regarded as an alternative treatment for SEGAs due to the complications of surgery. The present study primarily aimed to specify the effect of everolimus on SEGA volume change before and after treatment. The secondary objective was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients.
Materials & Methods: This pre- and post-treatment clinical trial was performed on 14 children (eight females and six males with a mean age of 10 years) previously diagnosed with TSC based on the diagnostic criteria. The subjects received oral everolimus at a dose of 3 mg/m2 for at least six months.
Results: Half of the patients had more than 30% of volume loss in SEGA, and in 28.5% of them, a ≥ 50% reduction in SEGA volume was observed (P=0.01). Moreover, 92.9% of the patients had a ≥ 50% decrease in the frequency of seizures (P=0.000). The response rate in AML and skin lesions was 14.2% and 50%, respectively.
Conclusion: Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients.

Keywords: Everolimus; Subependymal Giant Cell Astrocytoma; Tuberous Sclerosis Complex

DOI: https://doi.org/10.22037/ijcn.v15i4.30591

Cell Stress. 2021 Nov;5(11): 173-175

GRASPing the unconventional secretory machinery to bridge cellular stress signaling to the extracellular proteome.

Constantinos Demetriades, Julian Nuüchel, Markus Plomann.

Cellular adaptation to stress is a crucial homeostatic process for survival, metabolism, physiology, and disease. Cells respond to stress stimuli (e.g., nutrient starvation, growth factor deprivation, hypoxia, low energy, etc.) by changing the activity of signaling pathways, and interact with their environment by qualitatively and quantitatively modifying their intracellular, surface, and extracellular proteomes. How this delicate communication takes place is a hot topic in cell biological research, and has important implications for human disease.

Keywords: GRASP55; Golgi; Tuberous Sclerosis Complex (TSC); cellular stress response; mTORC1; rapamycin; unconventional protein secretion (UPS)

DOI: https://doi.org/10.15698/cst2021.11.259

MicroPubl Biol. 2021 ;2021

Drosophila yakuba - Tsc1.

Bailey Lose, Abigail Myers, Savanah Fondse, Ian Alberts, Joyce Stamm, James J Youngblom, Chinmay P Rele, Laura K Reed.

Gene Model for the ortholog of Tsc1 in the Drosophila yakuba DyakCAF1 assembly (GCA_000005975.1).

DOI: https://doi.org/10.17912/micropub.biology.000474

Elife. 2021 11 17. pii: e71575. [Epub ahead of print]10

Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.

María J Conde-Dusman, Partha N Dey, Óscar Elía-Zudaire, Luis G Rabaneda, Carmen García-Lira, Teddy Grand, Victor Briz, Eric R Velasco, Raül Andero, Sergio Niñerola, Angel Barco, Pierre Paoletti, John F Wesseling, Fabrizio Gardoni, Steven J Tavalin, Isabel Perez-Otaño.

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.

Keywords: BDNF; GIT1; GluN3A; NMDA receptor; cell biology; mTOR; memory; mouse; protein synthesis; rat; synapse

DOI: https://doi.org/10.7554/eLife.71575

Oxid Med Cell Longev. 2021 ;2021 6715758

mTORC1 Activation in Chx10-Specific Tsc1 Knockout Mice Accelerates Retina Aging and Degeneration.

Yu-Qing Rao, Yu-Tong Zhou, Wenchuan Zhou, Jia-Kai Li, Baojie Li, Jing Li.

Age-associated decline in retina function is largely responsible for the irreversible vision deterioration in the elderly population. It is also an important risk factor for the development of degenerative and angiogenic diseases. However, the molecular mechanisms involved in the process of aging in the retina remain largely elusive. This study investigated the role of mTORC1 signaling in aging of the retina. We showed that mTORC1 was activated in old-aged retina, particularly in the ganglion cells. The role of mTORC1 activation was further investigated in Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO). Activation of mTORC1 was found in bipolar and some of the ganglion and amacrine cells in the adult Tsc1-cKO retina. Bipolar cell hypertrophy and Müller gliosis were observed in Tsc1-cKO since 6 weeks of age. The abnormal endings of bipolar cell dendritic tips at the outer nuclear layer resembled that of the old-aged mice. Microglial cell activation became evident in 6-week-old Tsc1-cKO. At 5 months, the Tsc1-cKO mice exhibited advanced features of old-aged retina, including the expression of p16Ink4a and p21, expression of SA-β-gal in ganglion cells, decreased photoreceptor cell numbers, decreased electroretinogram responses, increased oxidative stress, microglial cell activation, and increased expression of immune and inflammatory genes. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. Collectively, our study showed that the activation of mTORC1 signaling accelerated aging of the retina by both cell autonomous and nonautonomous mechanisms. Our study also highlighted the role of microglia cells in driving the decline in retina function.

DOI: https://doi.org/10.1155/2021/6715758