scholarly journals Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Minqing Jiang ◽  
Lei Liu ◽  
Xuelian He ◽  
Haibo Wang ◽  
Wensheng Lin ◽  
...  
Keyword(s):  
Er Stress ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Stress Responses ◽  
Initial Increase ◽  
Oligodendrocyte Differentiation ◽  
Underlying Mechanisms ◽  
Apoptotic Pathways ◽  
Myelin Deficits ◽  
Mtor Signalling

Abstract Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; however, underlying mechanisms are not fully understood. TSC1/2 negatively regulate the function of mTOR, which is required for oligodendrocyte differentiation. Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses by activating a PERK–eIF2α signalling axis and Fas–JNK apoptotic pathways. Enhancement of the phospho-eIF2α adaptation pathway by inhibition of Gadd34-PP1 phosphatase with guanabenz protects oligodendrocytes and partially rescues myelination defects in Tsc1 mutants. Thus, TSC1-mTOR signalling acts as an important checkpoint for maintaining oligodendrocyte homoeostasis, pointing to a previously uncharacterized ER stress mechanism that contributes to hypomyelination in tuberous sclerosis.

scholarly journals Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38

2015 ◽  
Vol 89 (15) ◽  
pp. 7625-7635 ◽  
Author(s):  
Yadan Bai ◽  
Baoqin Xuan ◽  
Haiyan Liu ◽  
Jin Zhong ◽  
Dong Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tuberous Sclerosis ◽  
Human Cytomegalovirus ◽  
Tuberous Sclerosis Complex ◽  
Stress Responses ◽  
Mutational Analysis ◽  
Wild Type Virus ◽  
Cellular Environment ◽  
Successful Infection ◽  
Complex Protein

ABSTRACTThe mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and anabolic metabolism and is a critical host factor activated by human cytomegalovirus (HCMV) for successful infection. The multifunctional HCMV protein pUL38 previously has been reported to activate mTORC1 by binding to and antagonizing tuberous sclerosis complex protein 2 (TSC2) (J. N. Moorman et al., Cell Host Microbe 3:253–262, 2008,http://dx.doi.org/10.1016/j.chom.2008.03.002). pUL38 also plays a role in blocking endoplasmic reticulum stress-induced cell death during HCMV infection. In this study, we showed that a mutant pUL38 lacking the N-terminal 24 amino acids (pHA-UL3825–331) was fully functional in suppressing cell death during infection. Interestingly, pHA-UL3825–331lost the ability to interact with TSC2 but retained the ability to activate mTORC1, although to a lesser extent than full-length pHA-UL38. Recombinant virus expressing pHA-UL3825–331replicated with ∼10-fold less efficiency than the wild-type virus at a low multiplicity of infection (MOI), but it grew similarly well at a high MOI, suggesting an MOI-dependent importance of pUL38-TSC2 interaction in supporting virus propagation. Site-directed mutational analysis identified a TQ motif at amino acid residues 23 and 24 as critical for pUL38 interaction with TSC2. Importantly, when expressed in isolation, the TQ/AA substitution mutant pHA-UL38 TQ/AA was capable of activating mTORC1 just like pHA-UL3825–331. We also created TSC2-null U373-MG cell lines by CRISPR genome editing and showed that pUL38 was capable of further increasing mTORC1 activity in TSC2-null cells. Therefore, this study identified the residues important for pUL38-TSC2 interaction and demonstrated that pUL38 can activate mTORC1 in both TSC2-dependent and -independent manners.IMPORTANCEHCMV, like other viruses, depends exclusively on its host cell to propagate. Therefore, it has developed methods to protect against host stress responses and to usurp cellular processes to complete its life cycle. mTORC1 is believed to be important for virus replication, and HCMV maintains high mTORC1 activity despite the stressful cellular environment associated with infection. mTORC1 inhibitors suppressed HCMV replicationin vitroand reduced the incidence of HCMV reactivation in transplant recipients. We demonstrated that mTORC1 was activated by HCMV protein pUL38 in both TSC2-dependent and TSC2-independent manners. The pUL38-independent mode of mTORC1 activation also has been reported. These novel findings suggest the evolution of sophisticated approaches whereby HCMV activates mTORC1, indicating its importance in the biology and pathogenesis of HCMV.

Amino acids and mTOR signalling in anabolic function

2007 ◽  
Vol 35 (5) ◽  
pp. 1187-1190 ◽  
Author(s):  
C.G. Proud
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Ribosome Biogenesis ◽  
Mammalian Target Of Rapamycin ◽  
Single Amino Acid ◽  
Translational Machinery ◽  
Intracellular Amino Acids ◽  
Mtor Signalling

Amino acids regulate signalling through the mTORC1 (mammalian target of rapamycin, complex 1) and thereby control a number of components of the translational machinery, including initiation and elongation factors. mTORC1 also positively regulates other anabolic processes, in particular ribosome biogenesis. The most effective single amino acid is leucine. A key issue is how intracellular amino acids regulate mTORC1. This does not require the TSC1/2 (tuberous sclerosis complex 1/2) complex, which is involved in the activation of mTORC1, for example, by insulin. Progress in understanding the mechanisms responsible for this will be reviewed.

scholarly journals The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex

2016 ◽  
Vol 52 ◽  
pp. 12-20 ◽  
Author(s):  
Andrew R. Tee ◽  
Julian R. Sampson ◽  
Deb K. Pal ◽  
Joseph M. Bateman
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mtor Signalling

scholarly journals Tuberous Sclerosis Complex Activity Is Required to Control Neuronal Stress Responses in an mTOR-Dependent Manner

2009 ◽  
Vol 29 (18) ◽  
pp. 5926-5937 ◽  
Author(s):  
A. Di Nardo ◽  
I. Kramvis ◽  
N. Cho ◽  
A. Sadowski ◽  
L. Meikle ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Stress Responses ◽  
Dependent Manner ◽  
Complex Activity ◽  
Neuronal Stress

scholarly journals Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Filipe Palavra ◽  
Conceição Robalo ◽  
Flávio Reis
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Multiple Organ ◽  
Future Directions ◽  
Cell Functions ◽  
Organ Systems ◽  
Tumor Like Lesions ◽  
Mtor Signalling

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling

2003 ◽  
Vol 31 (3) ◽  
pp. 573-578 ◽  
Author(s):  
B.D. Manning ◽  
L.C. Cantley
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Complex Disease ◽  
Mammalian Target Of Rapamycin ◽  
Pi3k Pathway ◽  
Target Of Rapamycin ◽  
Gene Products ◽  
Phosphoinositide 3 Kinase ◽  
The Many ◽  
Mtor Signalling

The molecular interplay between the phosphoinositide 3-kinase (PI3K) pathway and mammalian target of rapamycin (mTOR) signalling in the control of cell growth and proliferation has been the subject of much interest and debate amongst cell biologists. A recent escalation of research in this area has come from the discovery of the tuberous sclerosis complex gene products, tuberin and hamartin, as central regulators of mTOR activation. The PI3K effector Akt/protein kinase B has been found to directly phosphorylate tuberin and is thereby thought to activate mTOR through inhibition of the tuberin–hamartin complex. The many recent studies aimed at defining the molecular nature of this revamped PI3K/Akt/mTOR pathway are reviewed here. The collective data discussed have laid the groundwork for important new insights into the many cancers caused by aberrant PI3K activation and the clinically challenging tuberous sclerosis complex disease and have suggested a possible means of treatment for both.

scholarly journals TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex

2020 ◽  
Vol 117 (4) ◽  
pp. 2170-2179 ◽  
Author(s):  
Magdalena Kedra ◽  
Katarzyna Banasiak ◽  
Katarzyna Kisielewska ◽  
Lidia Wolinska-Niziol ◽  
Jacek Jaworski ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Brain Anatomy ◽  
Childhood Epilepsy ◽  
Zebrafish Model ◽  
Cortical Malformations ◽  
Axonal Development ◽  
Expression Of Genes ◽  
Underlying Mechanisms ◽  
Tyrosine Receptor Kinase

Tuberous Sclerosis Complex (TSC) is a rare genetic disease that manifests with early symptoms, including cortical malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise during embryonic development and have been linked to childhood epilepsy before, but the underlying mechanisms of this relationship remain insufficiently understood. Zebrafish have emerged as a convenient model to study elementary neurodevelopment; however, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies of TANDs or new drug screening. In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions, which are homologous to the mammalian cortex. We observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. The lack of Tsc2 also delayed axonal development and caused aberrant tract fasciculation, corresponding to the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in nonmotor seizures and exhibited increased anxiety-like behavior. We further mapped discrete parameters of locomotor activity to epilepsy-like and anxiety-like behaviors, which were rescued by reducing tyrosine receptor kinase B (TrkB) signaling. Moreover, in contrast to treatment with vigabatrin and rapamycin, TrkB inhibition rescued brain dysconnectivity and anxiety-like behavior. These data reveal that commissural thinning results in the aberrant regulation of anxiety, providing a mechanistic link between brain anatomy and human TANDs. Our findings also implicate TrkB signaling in the complex pathology of TSC and reveal a therapeutic target.

scholarly journals Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2856
Author(s):  
James Moore ◽  
Ivan Osinnii ◽  
Amandine Grimm ◽  
Björn Oettinghaus ◽  
Anne Eckert ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Acute Phase Proteins ◽  
Cell Damage ◽  
Sirtuin 1 ◽  
Secretory Proteins ◽  
Unfolded Protein ◽  
Translation Error ◽  
Apoptotic Pathways ◽  
Main Component

Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of stress granules. Together, our results point to a concerted response to error-prone translation to alleviate ER stress in favor of activating alternative proteostasis mechanisms, most likely to avoid cell damage and apoptotic pathways, which would result from persistent activation of the ER and integrated stress responses.

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