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1.
Am J Hum Genet ; 110(3): 499-515, 2023 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-36724785

RESUMO

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.


Assuntos
Microcefalia , Transtornos dos Movimentos , Transtornos do Neurodesenvolvimento , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células HEK293 , Serina-Treonina Quinases TOR
2.
Nat Commun ; 13(1): 4836, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35977929

RESUMO

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.


Assuntos
Aminoácidos , Serina-Treonina Quinases TOR , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Aminoácidos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosforilação , Proteína Regulatória Associada a mTOR/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
3.
Cell Rep ; 33(5): 108329, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147468

RESUMO

The regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking affects multiple brain functions, such as learning and memory. We have previously shown that Thorase plays an important role in the internalization of AMPARs from the synaptic membrane. Here, we show that N-methyl-d-aspartate receptor (NMDAR) activation leads to increased S-nitrosylation of Thorase and N-ethylmaleimide-sensitive factor (NSF). S-nitrosylation of Thorase stabilizes Thorase-AMPAR complexes and enhances the internalization of AMPAR and interaction with protein-interacting C kinase 1 (PICK1). S-nitrosylated NSF is dependent on the S-nitrosylation of Thorase via trans-nitrosylation, which modulates the surface insertion of AMPARs. In the presence of the S-nitrosylation-deficient C137L Thorase mutant, AMPAR trafficking, long-term potentiation, and long-term depression are impaired. Overall, our data suggest that both S-nitrosylation and interactions of Thorase and NSF/PICK1 are required to modulate AMPAR-mediated synaptic plasticity. This study provides critical information that elucidates the mechanism underlying Thorase and NSF-mediated trafficking of AMPAR complexes.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Membrana Celular/metabolismo , Proteínas Sensíveis a N-Etilmaleimida/metabolismo , Receptores de AMPA/metabolismo , Adenosina Trifosfatases/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Ciclo Celular/metabolismo , Cisteína/metabolismo , Endocitose/efeitos dos fármacos , Glutationa/metabolismo , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Metilaspartato/farmacologia , Plasticidade Neuronal , Óxido Nítrico/metabolismo , Nitrosação , Ligação Proteica , Multimerização Proteica , Transporte Proteico , S-Nitrosoglutationa/metabolismo
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